JP6838052B2 - Tricyclic Condensed Pyridine-2-one Derivatives and Their Use as BRD4 Inhibitors - Google Patents

Description

The present disclosure relates to the field of pharmaceutical chemistry, and more particularly to the development of compounds as inhibitors of one or more BET family bromodomains. The present disclosure relates to a heterocyclic compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing them as an active ingredient.

The present disclosure further relates to the synthesis and characterization of the aforementioned compounds and the study of their anti-cancer activity. The compounds of the present disclosure are useful as pharmaceuticals for the treatment, prevention or control of diseases or diseases mediated by one or more BET family bromodomains and are used in the manufacture of pharmaceuticals.

Transcriptional regulation is a major event in cell differentiation, proliferation and apoptosis. The transcriptional activity of a pair of genes determines cell function and is tightly regulated by various factors. One of the regulatory mechanisms involved in this process is a change in the tertiary structure of DNA, which affects transcription factors for these target DNA linkages. Nucleosome integrity is regulated by the acetylation status of core histones, resulting in transcription tolerance. Transcription factor regulation is thought to be associated with changes in chromatin structure. By altering the affinity of histone proteins for coiled DNA in nucleosomes, the structure of chromatin is altered. It is believed that hypoacetylated histones have greater affinity for DNA, forming tightly bound DNA-histone complexes and making DNA inaccessible to transcriptional regulation. The acetylation state of histones is governed by the equilibrium activity of histone acetyltransferase (HAT) and histone deacetylase (HDAC). A family of Bromodomain and Extra-Terminal proteins, called BET proteins, is a leader in the acetyl state of histones, altering chromatin structure and gene expression.

The BET family of bromodomain-containing proteins includes four proteins that are widely expressed in various tissues, with the exception of BRDT localized in the testis: BRD2, BRD3, BRD4 and BRDT. Each BRD protein contains a tandem bromodomain capable of binding to acetylated lysine residues in histones H3 and H4. It has been reported that BRD2 and BRD3 associate with histones along genes that are actively transcribed and are involved in promoting transcription elongation (Non-Patent Document 1), and BRD4 is phosphorylation of RNA polymerase II. It has been reported that it is involved in the recruitment of pTEF-β complex to nucleosomes, which causes transcriptional elongation of adjacent genes (Non-Patent Document 2).

BRD4 or BRD3 can fuse with NUTs that form novel fusion oncogenes BRD4-NUT or BRD3-NUT (nuclear proteins in the testis) in highly malignant forms of epithelial neoplasms (Non-Patent Document 3 and Non-Patent). Document 4). The data suggest that the BRD-NUT fusion protein contributes to carcinogenesis (Non-Patent Document 5). BET proteins, including BRD4, have been shown to be important regulators of gene expression profiles in multiple diseases such as cancer, diabetes, obesity, cardiovascular and renal impairment. Currently, some BRD4 inhibitors are in various stages of clinical trials for cancers such as IBET-762, JQ1, OTX-015 and RVX-2135 (Non-Patent Documents 6 and 7).

Patent Document 1 discloses a tricyclic aryl compound as a squalene synthase inhibitor for treating hypercholesterolemia, hypertriglyceridemia and hypoHDL cholesterolemia and / or arteriosclerosis.

Ichikawa Masanori et al. Have published a paper (Non-Patent Document 8) describing the squalene synthase inhibitor DF4611 (B). Nils Griebenow et al. Also reported the synthesis of novel 4H, 6H- [2] benzoxepino [4,5-c] [1,2] oxazole (C) as a squalene synthase inhibitor (Non-Patent Document 9).

There are several drug-based chemotherapy and targeted therapies for cancer, but it is difficult to see that they are effective treatments for cancer. In addition, acquired tolerance and the development of disease recurrence are still important issues that must be addressed. Although some bromodomain inhibitors are known clinically and preclinically, there is still a need to find potent bromodomain inhibitors with the desired drug-like properties.

PCT Publication No. 2008133288

Leroy et al., Mol. Cell, 2008, Volume 30 (1): pp. 51-60 Hargreaves et al., Cell, 2009, 138 (1), pp. 129-145 French et al., Cancer Research, 2003, Volume 63, pp. 304-307 French et al., Journal of Clinical Oncology, 2004, 22 (20), 4135-4139. Oncogene, 2008, Vol. 27, pp. 2237-2242 P. Filmapakopoulos et al., Nature Review Drug Discovery, Vol. 13, 2014, pp. 337-356. M. Brand et al., ACS Chem. Biol, Volume 10, 2015, pp. 22-39 Ichikawa Masanori et al., ACS Med. Chem. Lett. , 2013, pp. 923-936 Nils Greenow et al., Bioorg. Med. Chem. Lett. Volume 21, 2011, pp. 3648-3653

Therefore, the present invention provides a novel drug-like molecule having excellent efficacy as a BRD4 inhibitor capable of inhibiting the binding of histone acetylated lysine residues for controlling gene expression in various diseases. To do.

The present disclosure is based on the development of compounds of formula (I) (see below) that exhibit advantageous anti-cancer properties. Accordingly, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

Here, ---- is absent or a single bond, X is -O -, - is selected from N- or -S-, n is Less than six, _{R 1} is hydrogen, halogen, C _Has heteroatoms selected from 1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, N, O, S Selected from the group consisting of C _{1-6 alkoxyalkyl, where C 1-6} alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl can optionally be hydrogen, C _1- Substituted with one or more groups selected from _{6 alkyl, halogen, OH, R 2} and R ₃ are independently hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), Thioxo (= S), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, arylalkoxy, C _3-8 cycloalkyl, C _{3 -8} Cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , −N (R _a ) SO ₂ R _b , −NR _a C (O) OR _b , −NR _a R _b , −NR _a C (O) R _b −, NR _a C (S) R _b −, −SONR _a R _b- , -SO ₂ NR _a R _b- , -OR _{a , -OR a} C (O) OR _b- , -OC (O) NR _a R _b , OC (O) R _a , -OC (O) _{) NR a R b -, -} R a NR b R c, -R a oR b -, - SR a, are selected from -SOR _a, or _-SO 2 _{R a, wherein,} R a, _{R b,} and _{R c Are} independent hydrogen, C _1-6 alkyl, C 3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _2-6. is selected from heteroarylalkyl, _{R 4} is _{hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 5-6} a Selected from the group consisting of _{C 1-6} alkoxyalkyls having heteroatoms selected from reels, C _1-6 heteroaryls, N, O, S _{, where C 1-6} alkyls, C _3-8 cycloalkyls. , C _5-6 aryl, C _2-6 heteroaryl are optionally substituted with one or more groups selected from _{hydrogen, C 1-6} alkyl, C _{3-8 cycloalkyl, halogen, OH and cyano.} Ring A has C _1-6 heteroaryl, C _3-8 cycloalkyl, C _3-10 cycloaryl, C _{4-6 heterocycloalkyl and C 4-10} having a hetero atom selected from N, O, S. Selected from the group consisting of heterocycloaryl, Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , -NSO ₂ R ₆ or -O-CO-NR ₅ R ₆ selected from R ₅ , R ₆ and R ₇ independently hydrogen or substituted or unsubstituted C _{5 -6 aryl, C 1-6} is selected from _{heteroaryl, C 3-8} cycloalkyl, and _{C 1-6} alkyl, wherein _R 5, _{if R 6} and _{R 7} are substituted, one or more substituents Hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), thioxo (= S), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _{1 6} alkoxy, C _1-6 haloalkoxy, C _5-6 aryl alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl , Alkylamino, -COOR _a , -C (O) R _b ,-(S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR ^a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _a C (S) R _b- , -SONR _a R _b- , -SO ₂ NR _a R _b- , -OR _a , -R _a C (O) OR _b −, −OC (O) NR _a R _b , OC (O) R _{a, -OC (O) NR a} R b -, - R a NR b R c, -R a OR b -, - SR a, are selected from -SOR _a, or _-SO 2 _{R a,} wherein, _{R a} , R _b and R _c are hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C. Selected from _{1-6 heteroarylalkyl.}

The present disclosure relates to compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with a carrier.
The present disclosure comprises the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, along with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions. Regarding.

The present disclosure further relates to methods of preventing or treating proliferative disorders by administering a therapeutically effective amount of a novel compound of formula (I) or a pharmaceutically acceptable salt and / or prodrug.
The present disclosure relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

These and other features, aspects, and advantages of this subject will be better understood by reference to the following description. This overview is provided to provide a simplified introduction to the selection of concepts. This overview is not intended to identify the material or essential features of the present disclosure and is not intended to be used to limit the scope of the subject matter.

Those skilled in the art will recognize that this disclosure is subject to modifications and alterations other than those specifically described. It should be understood that this disclosure includes all such modifications and modifications. The present disclosure also includes all of such steps, features, compositions and compounds individually or collectively referred to or indicated herein, and any and all of one or more of such steps or features. Including the combination of.
[Definition]
For convenience, specific terms and examples used herein are summarized herein before further description of this disclosure. These definitions should be read and understood by those skilled in the art in the light of the rest of this disclosure. The terms used herein have meanings recognized and known to those skilled in the art, but for convenience and completeness, certain terms and their meanings are set forth below.

The articles "a,""an," and "the" are used to refer to one or more (ie, at least one) grammatical objects of the article.
The terms "comprise" and "comprising" are used in a comprehensive and open sense to mean that additional elements may be included. Throughout the specification, unless otherwise required by the context, the term "comprise" and any modification such as "comprising" include the described elements or steps or groups of elements or steps. However, it should be understood that it does not exclude other elements or steps or groups of elements or steps.

The term "inclusion" is used to mean "listed, but not limited to". "Listed" and "listed, but not limited to" are used interchangeably.

Unless otherwise specified, the following terms have the indicated meanings in the structural formulas given herein and throughout the disclosure.
The term "alkyl" refers to a straight or branched aliphatic hydrocarbon chain having 1 to 6 carbon atoms. The term is exemplified by groups such as n-butyl, iso-butyl, t-butyl, n-hexyl and the like. These groups may be optionally substituted.

The term "aryl" refers to an aromatic radical having 5 to 10 carbon atoms having a single ring (eg, phenyl) or multiple rings (eg, biphenyl) or a polycondensed (fusion) ring (eg, naphthyl or anthranyl). Refers to, which may optionally be substituted with one or more substituents. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, indanyl, biphenyl and the like.

The term "arylalkyl" refers to an aryl group directly attached to an alkyl group, which may optionally be substituted with one or more substituents. Preferred arylalkyl groups include, but are not limited to _{, -CH 2} C ₆ H ₅ , -C ₂ H ₄ C ₆ H _{5, and the like.}

The term "heterocyclyl" refers to a heterocyclic ring radical that may optionally be substituted with one or more substituents. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom so as to result in the formation of a stable structure.

Further, the term "heterocyclyl" refers to a stable 2-6 membered ring radical consisting of a carbon atom and 1-5 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For the purposes of the present invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, and nitrogen, phosphorus, carbon, oxygen or in the heterocyclic ring radical. Sulfur atoms may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized and the ring radicals may be partially or completely saturated. Preferred heterocyclyl groups are azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indridinyl, naphthyldinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pyrazolyl, pyridyl, Pteridinyl, prynyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, homopiperazinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidinyl, pyrrolidinyl, pyrazinyl Oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinucridinyl, isothiazolydinyl, indrill, isoindrill, indolinyl, isoindrinyl, octahydroindrill, octahydroisoindrill, quinolyl, Examples thereof include isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, thienyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, furyl, tetrahydrofuryl, tetrahydropyranyl, chromanyl and isochromanyl. , Not limited to these.

The term "heteroaryl" refers to a complex aromatic carbocyclic group of 1 to 6 carbon atoms having a single ring (eg, pyridine) or multiple rings (eg, isoquinoline) or multiple fused rings. Preferred heteroaryls include thiophene, pyrazole, thiazole, pyridine and the like. These groups may be optionally substituted.

The term "heteroarylalkyl" refers to a heteroaryl group directly attached to an alkyl group, which may optionally be substituted with one or more substituents. Preferred heteroarylalkyl groups include, _{but are not limited to, CH 2} -pyridinyl, -C ₂ H ₄ -furyl and the like.

The term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system of about 3-12 carbon atoms, which may optionally be substituted with one or more substituents. A polycyclic ring means a hydrocarbon system containing two or more ring systems that share one or more ring carbon atoms, that is, a spiro structure, a condensed structure, or a crosslinked structure. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctanyl, perhydronaphthyl, adamantyl, noradamantyl and norbornyl groups, crosslinked cyclic or spirocyclic groups such as spiro [4.4] non. -2-Il and the like, but not limited to these.

The term "alkoxy" refers to an alkyl group attached to the rest of the molecule via an oxygen bond, which may optionally be substituted with one or more substituents. Preferred alkoxy groups include, but are not limited to _{, -OCH 3} , -OC ₂ H _{5, and the like.}

The term "alkylthio" refers to an alkyl group attached to the rest of the molecule via a sulfur bond, which may optionally be substituted with one or more substituents. Preferred alkylthio groups include, but are not limited to _{, -SCH 3} , -SC ₂ H _{5, and the like.}

The term "alkylamino" refers to the alkyl group as defined above attached to the rest of the molecule via an amino bond, which may optionally be substituted with one or more substituents. Preferred alkylamino groups include, but are not limited to _{, -NHCH 3} , -N (CH ₃ ) _{2, and the like.}

"Halo" or "halogen", alone or in combination with any other term, means halogens such as chloro (Cl), fluoro (F), bromo (Br) and iodine (I).
The compound of formula (I) is a derivative, analog, tautomer, stereoisomer, diastereomer, geometric isomer, polymorph, solvate, intermediate, metabolite, prodrug or pharmacy. It may be a pharmaceutically acceptable salt and composition.

The compounds described herein may contain one or more chiral centers and / or double bonds, and thus double bond isomers (ie, geometric isomers), positional isomers, enantiomers or It may exist as a steric isomer such as a diastereomer. Thus, the chemical structures presented herein are stereoisomerically pure forms (eg, geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomers and sterics. Includes all possible enantiomers and stereoisomers of the exemplified or identified compounds, including mixtures of isomers. Mixtures of enantiomers and stereoisomers may be split into enantiomers or stereoisomers of their components using separation techniques or chiral synthesis techniques well known to those skilled in the art. The compound may also be present in several tautomeric forms, including the enol form, the keto form and mixtures thereof. Thus, the chemical structures presented herein include all possible tautomeric forms of the exemplified or identified compounds. It is also understood that some isomer forms, such as diastereomers, enantiomers and geometric isomers, can be separated by physical and / or chemical methods by those skilled in the art. The pharmaceutically acceptable solvate may be a hydrate or may contain other crystallization solvents such as alcohols and ethers.

As used herein, the term "solvate" refers to the crystalline form of a substance containing a solvent.
The term "hydrate" refers to a solvate in which the solvent is water.
The phrase "pharmaceutically acceptable" includes, but is not limited to, gastric upset or dizziness when administered to a mammal, which is physiologically acceptable and typically allergic or similar. Refers to a compound or composition that does not cause an inappropriate reaction.

The pharmaceutically acceptable salts that form part of the present invention are salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn, N, N'-. Salts of organic bases such as diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, α-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine Can be mentioned. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine and the like. Salts, where appropriate, are sulfates, nitrates, phosphates, perchlorates, borates, hydrohalogenates, acetates, tartrates, maleates, citrates, succinates, palmos. It may contain acid addition salts such as acid salts, methanesulfonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. ..

As used herein, the term "substituted" is intended to include all acceptable substituents on the organic compound. In a wide range of embodiments, acceptable substituents include acyclic and cyclic, branched and non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described above. Acceptable substituents may be one or more identical or different for suitable organic compounds. For the purposes of the present disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any acceptable substituents of the organic compounds described herein that satisfy the valence of the heteroatom. Good.

The term "effective amount" means an amount of compound or composition sufficient to significantly and positively alter the condition and / or disease to be treated (eg, provide a positive clinical response). The effective amount of active ingredient for use in a pharmaceutical composition depends on the particular disease being treated, the severity of the disease, the duration of treatment, the nature of the combination therapy, the particular active ingredient used, and the particular active ingredient used. It depends on the particular pharmaceutically acceptable excipient / carrier, route of administration, and similar factors within the knowledge and expertise of the attending physician.

The compounds described herein can also be prepared in any solid or liquid physical form, eg, this compound is in crystalline form, amorphous form and has any particle size. .. In addition, the compound particles may be micronized or nano-sized, or may be in agglomerated, granular granules, powders, oils, oily suspensions or other forms of solid or liquid physical forms. ..

The compounds described herein may exhibit polymorphism. The present invention further comprises different polymorphs of the compounds of the present invention.
The term "polymorph" refers to the crystalline form of the same molecule, where different polymorphs are the melting temperature, heat of fusion, solubility, melting rate and / or vibration spectrum resulting from the arrangement or conformation of the molecules in the crystal lattice. It may have different physical properties such as.

The term "prodrug" refers to a precursor of a compound of formula (I) that undergoes a chemical conversion by a metabolic step before becoming an active pharmacological substance. In general, such prodrugs are functional derivatives of the compounds of the invention and can be easily converted to the compounds of the invention in vivo.

The present disclosure describes compounds of formula (I), or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active substances and Regarding pharmaceutically active derivatives.

Here, ---- is absent or a single bond, X is -O -, - is selected from N- or -S-, n is Less than six, _{R 1} is hydrogen, halogen, C _Has heteroatoms selected from 1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, N, O, S Selected from the group consisting of C _{1-6 alkoxyalkyl, where C 1-6} alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl can optionally be hydrogen, C _1- Substituted with one or more groups selected from _{6 alkyl, halogen, OH, R 2} and R ₃ are independently hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), Thioxo (= S), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, arylalkoxy, C _3-8 cycloalkyl, C _{3 -8} Cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , −N (R _a ) SO ₂ R _b , −NR _a C (O) OR _b , −NR _a R _b , −NR _a C (O) R _b −, NR _a C (S) R _b −, −SONR _a R _b- , -SO ₂ NR _a R _b- , -OR _{a , -OR a} C (O) OR _b- , -OC (O) NR _a R _b , OC (O) R _a , -OC (O) _{) NR a R b -, -} R a NR b R c, -R a oR b -, - SR a, are selected from -SOR _a, or _-SO 2 _{R a, wherein,} R a, _{R b,} and _{R c} Independently, hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _{2- Selected from 6} heteroarylalkyl, R ₄ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _5-6. Selected from the group consisting of _{C 1-6} alkoxyalkyl having hetero atoms selected from aryl, C _1-6 heteroaryl, N, O, S _{, where C 1-6} alkyl, C _3-8 cycloalkyl. , C _5-6 aryl, C _2-6 heteroaryl are optionally substituted with one or more groups selected from _{hydrogen, C 1-6} alkyl, C _{3-8 cycloalkyl, halogen, OH and cyano.} Ring A has C _1-6 heteroaryl, C _3-8 cycloalkyl, C _3-10 cycloaryl, C _{4-6 heterocycloalkyl and C 4-10} having a hetero atom selected from N, O, S. Selected from the group consisting of heterocycloaryl, Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , -NSO ₂ R ₆ or -O-CO-NR ₅ R ₆ where R ₅ , R ₆ and R ₇ are independently hydrogen or substituted or unsubstituted. C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl, where one or more if _{R 5} , R ₆ and R _{7 are substituted.} Substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), thioxo (= S), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 aryl alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _{1- 6} Heteroaryl, Alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , _{-NR a R b, -NR a C} (O) R b -, NR a C (S) R b -, - SONR a R b -, - SO 2 NR a R b -, - OR a, -OR a C (O) OR _b −, −OC (O) NR _a R _{b , OC (O) R a,} -OC (O) NR a R b -, - R a NR b R c, -R a OR b -, - SR a, are selected from -SOR _a, or _-SO 2 _{R a} Here, _Ra , R _b and R _c are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6. It is selected from heterocyclyl, C _1-6 heteroaryl or C _{1-6 heteroarylalkyl.}

According to one embodiment, the present disclosure describes a compound of formula (I) or a steric isomer thereof, a pharmaceutically acceptable salt, complex, hydrate, alkoxylate, tally mutant, polymorph, racemic. For mixtures, optically active substances and pharmaceutically active derivatives, where --- is absent or single-bonded, X is selected from -O- or -N-, and n is 0-6. , R ₁ are hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, N, O , S selected from the group consisting of _{C 1-6 alkoxyalkyls having heteroatoms, where C 1-6} alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 hetero Aryl is optionally substituted with one or more groups selected from _{hydrogen, C 1-6 alkyl, halogen, OH, and R 2} and R ₃ are independently hydrogen, halogen, hydroxy, nitro, cyano, azido, nitroso, oxo (= O), thioxo _{(= S), - SO 2} -, amino, hydrazino, _{formyl, C 1-6} alkyl, _{haloalkyl, C 1-6 alkoxy, C 1-6} haloalkoxy, arylalkoxy , C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _{a C (S) R b -,} - SONR a R b -, - SO 2 NR a R b -, - OR a, -OR a C (O) OR b -, - OC (O) NR a R b, OC _{(O) R a, -OC (} O) NR a R b -, - R a NR b R c, -R a oR b -, - SR a, are selected from -SOR _a, or _-SO 2 _{R a,} where R _a , R _b and R _c are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 hetero. Independently selected from cyclyl, C _1-6 heteroaryl or C _{2-6 heteroarylalkyl, R 4} is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _{5 -6 aryl, C 1-6} heteroaryl, N, O, selected from the group consisting of _{C 1-6} alkoxyalkyl having hetero atoms selected from S, _{wherein, C 1-6 alkyl, C 3-8} Cycloalkyl, C _5-6 aryl, C _2-6 heteroaryl are optionally substituted with one or more groups selected from _{hydrogen, C 1-6} alkyl, C _{3-8 cycloalkyl, halogen, OH and cyano.} is ring _{a, C 4} with _{C 1-6 heteroaryl, C 3-8 cycloalkyl, C 3-10} cycloalkyl _{aryl, C 4-6} heterocycloalkyl and N, O, heteroatoms selected from S Selected from the group consisting of _{-10 heterocycloaryl, Z is -CH 2} OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR. Selected from ₆ R ₇ , -NR ₅ COR _{6 , -NSO 2} R ₆ or -O-CO-NR ₅ R ₆ , R ₅ , R ₆ and R ₇ are independently hydrogen or substituted or unsubstituted. One or more selected from C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl, where R ₅ , R ₆ and R _{7 are substituted.} Substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), thioxo (= S), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C. _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 aryl alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 Heteroaryl, Alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b ,- NR _a R _b , -NR _a C (O) R _{b -, NR a C (S} ) R b -, - SONR a R b -, - SO 2 NR a R b -, - OR a, -OR a C (O) OR b -, - OC (O) NR _{a R b, OC (O)} R a, -OC (O) NR a R b -, - R a NR b R c, -R a oR b -, - SR a, -SOR a , or _-SO 2 _{R a} Selected from, where _Ra , R _b and R _c are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C. It is selected from _2-6 heterocyclyl, C _1-6 heteroaryl or C _{1-6 heteroarylalkyl.}

According to other embodiments, the present disclosure relates to compounds of formula (I) or steric isomers thereof, pharmaceutically acceptable salts, complexes, hydrates, alkoxys, arylates, polymorphs, For racemic mixtures, optically active substances and pharmaceutically active derivatives, where --- is absent or single-bonded, X is selected from -O- or -N-, and n is 0-6. Yes, R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, N, Selected from the group consisting of alkoxyalkyls having heteroatoms selected from O, S, where C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl Optionally substituted with one or more groups selected from hydrogen, C _{1-6 alkyl, halogen, OH, R 2} and R ₃ are independently hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso. , Oxo (= O), thioxo (= S), -SO _2- , amino, hydradino, formyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl Alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _{a C (S) R b -} , - SONR a R b -, - SO 2 NR a R b -, - OR a, -OR a C (O) OR b -, - OC (O) NR a R b, _{OC (O) R a, -OC} (O) NR a R b -, - R a NR b R c, -R a oR b -, - SR a, are selected from -SOR _a, or _-SO 2 _{R a,} Here, R _a , R _b and R _c are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 hete. _{Roshikuriru, C 1-6} is selected from heteroaryl or _{C 1-6} heteroarylalkyl, _{R 4 is, C 1-6} alkyl, _{haloalkyl, C 3-8 cycloalkyl, C 5-6 aryl, C 1-6} heteroaryl Selected from the group consisting of alkoxyalkyls having heteroatoms selected from aryl, N, O, S, where C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 Heteroaryls are optionally _{substituted with one or more groups selected from hydrogen, C 1-6} alkyl, halogen, OH and cyano, and ring A is thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, Selected from pyrazolyl, oxazolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, thiadiazolyl or frill, Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , -NSO ₂ R ₆ or -O-CO-NR ₅ R ₆ , R ₅ , R ₆ and R ₇ are independent. Selected from hydrogen or substituted or unsubstituted C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl, where R ₅ , R ₆ and R ₇ are substituted. If so, one or more substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), thioxo (= S), -SO _2- , amino, hydrazino, formyl, C _{1 -6} alkyl, _{haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 5-6 arylalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 5-6 aryl, C 2- 6} Heterocyclyl, C _1-6 Heteroaryl, Alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _a C (S) R _b- , -SONR _a R _b -, -SO ₂ NR _a R _b- , -OR _{a , -OR a} C (O) OR _b- , -OC (O) NR _a R _b , OC (O) R _a , -OC (O) NR _{a R b -, - R a NR} b R c, -R a oR b -, - SR a, are selected from -SOR _a, or _-SO 2 _{R a, wherein,} R a, _{R b,} and _{R c} are independently Then hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroaryl. Selected from alkyl.

According to one embodiment, the present disclosure describes compounds of formula (I) or steric isomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, heteromutants, polymorphs, racemics. For mixtures, optically active substances and pharmaceutically active derivatives, where --- is a single bond, X is -N-, n is 0-6, R ₁ is C _{1-. 6} Alkoxy, where C _1-6 alkyl is optionally substituted with one or more groups selected from _{hydrogen, C 1-6 alkyl, halogen, OH, and R 2} and R ₃ are independent. Selected from hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy, R ₄ is C _1-6 alkyl, haloalkyl, C _{3- Selected from the group consisting of 8} cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, alkoxyalkyl with heteroatoms selected from N, O, S, where C _1-6 alkyl, C _{3- 8} Cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl are optionally _{substituted with one or more groups selected from hydrogen, C 1-6} alkyl, halogen, OH and cyano, and ring A is: Selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, pyrazolyl, oxazolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, thiadiazolyl or frill, Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , -NSO ₂ R ₆ or -O-CO-NR ₅ R ₆ R ₅ , R ₆ and R ₇ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl.
Here, when R ₅ , R ₆ and R ₇ are substituted, one or more substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), tioxo (= S). , -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 arylalkoxy, C _3-8 cycloalkyl, C _{3- 8} Cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _2-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C ( O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b ,- N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _a C (S) R _b- , -SONR _a R _b −, −SO ₂ NR _a R _b −, _{−OR a} , −OR _a C (O) OR _b −, −OC (O) NR _a R _b , OC (O) R _a , −OC (O) _{NR a R b -, - R} a NR b R c, -R a oR b -, - SR a, are selected from -SOR _a, or _-SO 2 _{R a, wherein,} R a, _{R b,} and _{R c} , Independently, hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6. Selected from heteroarylalkyl.

According to one embodiment, the present disclosure describes compounds of formula (I) or steric isomers thereof, pharmaceutically acceptable salts, complexes, hydrates, alkoxys, tautomers, polymorphs, racemics. For mixtures, optically active substances and pharmaceutically active derivatives, where --- is absent, X is -O-, n is 0-6, R ₁ is C _1-6. Alkoxy, where C _1-6 alkyl is optionally substituted with one or more groups selected from _{hydrogen, C 1-6 alkyl, halogen, OH, and R 2} and R ₃ are independent. Selected from hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy, R ₄ is C _1-6 alkyl, haloalkyl, C _{3 Selected from the group consisting of -8} cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, alkoxyalkyl having a hetero atom selected from N, O, S, where C _1-6 alkyl, C _{The 3-8} cycloalkyl, C _5-6 aryl, and C _1-6 heteroaryl are optionally _{substituted with one or more groups selected from hydrogen, C 1-6} alkyl, halogen, OH and cyano, and ring A. Is selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl or frill, Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R. ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , -NSO ₂ R ₆ or -O-CO-NR ₅ R ₆ , R ₅ , R ₆ and R ₇ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl. Where R ₅ , R ₆ and R ₇ are substituted, the one or more substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), tioxo (= S). ), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 arylalkoxy, C _3-8 cycloalkyl, C _{3 -8} Cycloalkyloxy, C _{5 -6aryl} , C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _a C (S) R _b- , -SONR _a R _b- , -SO ₂ NR _a R _b- , -OR _{a , -OR a} C (O) OR _b- , -OC (O) NR _a R _b , OC (O) R _a , -OC (O) NR _a R _b -,- _{R a NR b R c, -R} a oR b -, - SR a, are selected from -SOR _a, or _-SO 2 _{R a, wherein,} R a, _{R b,} and _{R c} are independently hydrogen, Selected from C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _{1-6 heteroaryl alkyl} ..

According to one embodiment, the present disclosure discloses compounds of formula (I) or steric isomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, copolymers, polymorphs, racemics. For mixtures, optically active compounds and pharmaceutically active derivatives, where --- is a single bond, X is -N-, n is 1-2, and R ₁ is C _1-4. Alkyl, R ₂ and R ₃ are independently selected from hydrogen, C _1-4 alkyl or C _1-4 alkoxy, and R ₄ consists of C _3-8 cycloalkyl or C _5-6 aryl. Selected from the group, where C _3-8 cycloalkyl or C _5-6 aryl is substituted with one or more groups selected from hydrogen, C _1-6 alkyl, halogen and cyano, ring A is thienyl. , Thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl or frills, where Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , -NSO ₂ R ₆ or -O-CO-NR ₅ R ₆ selected from R ₅ , R ₆ and R ₇ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl. When R ₅ , R ₆ and R ₇ are substituted in, one or more substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), thioxo (= S), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 arylalkoxy, C _3-8 cycloalkyl, C _3-8 Cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) ) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _a C (S) R _b- , -SONR _a R _b- , -SO ₂ NR _a R _b- , -OR _a , _{-OR a C (O) OR b} -, - OC (O) NR a R b, OC (O) R a, -OC (O) NR a R b -, - R a NR b R c, -R a oR _{b -,} - SR _a, are selected from -SOR _a, or _-SO 2 _{R a, wherein,} R a, _{R b,} and _{R c} are independently _{hydrogen, C 1-6 alkyl, C 3-8} It is selected from cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroaryl alkyl.

According to other embodiments, the present disclosure describes compounds of formula (I) or steric isomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, arylates, polymorphs, For racemic mixtures, optically active compounds and pharmaceutically active derivatives, where --- is absent, X is -O-, n is 1-2, and R ₁ is C _1-4. Alkyl, R ₂ and R ₃ are independently selected from hydrogen, C _1-4 alkyl or C _1-4 alkoxy, and R ₄ consists of C _3-8 cycloalkyl or C _5-6 aryl. Selected from the group, where C _3-8 cycloalkyl or C _5-6 aryl is substituted with one or more groups selected from hydrogen, C _1-6 alkyl, halogen and cyano, ring A is thienyl. , Thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl or frills, where Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , -NSO ₂ R ₆ or -O-CO-NR ₅ R ₆ selected from R ₅ , R ₆ and R ₇ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl. When R ₅ , R ₆ and R ₇ are substituted in, one or more substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), thioxo (= S), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 arylalkoxy, C _3-8 cycloalkyl, C _3-8 Cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) ) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _a C (S) R _b- , -SONR _a R _b- , -SO ₂ NR _a R _b- , -OR _a , _{-OR a C (O) OR b} -, - OC (O) NR a R b, OC (O) R a, -OC (O) NR a R b -, - R a NR b R c, -R a oR _{b -,} - SR _a, are selected from -SOR _a, or _-SO 2 _{R a, wherein,} R a, _{R b,} and _{R c} are independently _{hydrogen, C 1-6 alkyl, C 3-8} It is selected from cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroaryl alkyl.

According to other embodiments, the present disclosure describes compounds of formula (I) or steric isomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tally mutants, polymorphs, and the like. For racemic mixtures, optically active compounds and pharmaceutically active derivatives, where --- is absent, X is -S-, n is 1-2, and R ₁ is C _1-4. Alkyl, R ₂ and R ₃ are independently selected from hydrogen, C _1-4 alkyl or C _1-4 alkoxy, and R ₄ consists of C _3-8 cycloalkyl or C _5-6 aryl. Selected from the group, where C _3-8 cycloalkyl or C _5-6 aryl is substituted with one or more groups selected from hydrogen, C _1-6 alkyl, halogen and cyano, ring A is thienyl. , Thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl or frills, where Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , -NSO ₂ R ₆ or -O-CO-NR ₅ R ₆ selected from R ₅ , R ₆ and R ₇ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl. When R ₅ , R ₆ and R ₇ are substituted in, one or more substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), thioxo (= S), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 arylalkoxy, C _3-8 cycloalkyl, C _3-8 Cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) ) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _a C (S) R _b- , -SONR _a R _b- , -SO ₂ NR _a R _b- , -OR _a , _{-OR a C (O) OR b} -, - OC (O) NR a R b, OC (O) R a, -OC (O) NR a R b -, - R a NR b R c, -R a oR _{b -,} - SR _a, are selected from -SOR _a, or _-SO 2 _{R a, wherein,} R a, _{R b,} and _{R c} are independently _{hydrogen, C 1-6 alkyl, C 3-8} It is selected from cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroaryl alkyl.

According to one embodiment, the present disclosure describes compounds of formula (I) or steric isomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tally mutants, polymorphs, racemics. For mixtures, optically active compounds and pharmaceutically active derivatives, where --- is a single bond, X is -N-, n is 1-2 and R ₁ is a C ₁ alkyl. Yes, R ₂ and R ₃ are independently selected from hydrogen, C _1-2 alkyl or C _1-2 alkoxy, and R ₄ is from the group consisting of _{C 3-8} cycloalkyl or C _{5-6 aryl.} Selected, where C _3-8 cycloalkyl or C _5-6 aryl is substituted with one or more groups selected from hydrogen, C _1-6 alkyl, halogen and cyano, ring A is thienyl, thiazolyl. , Pyrizinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl or pyrazolyl, Z is selected from -CH ₂ OR _5, -COOR ₅ , -CONR ₅ R ₆ , or -NR ₅ R ₆ and R ₅ and R ₆ are , Independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl and C _1-6 alkyl, where R ₅ and R ₆ are substituted, the substituent is hydrogen, halogen. , Hydroxy, nitro, cyano or C _1-6 alkyl.

According to one embodiment, the present disclosure discloses compounds of formula (I) or steric isomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tally mutants, polymorphs, racemics. For mixtures, optically active compounds and pharmaceutically active derivatives, where --- is absent, X is -O-, n is 1-2, and R ₁ is C ₁ alkyl. , R ₂ and R ₃ are independently selected from hydrogen, C _1-2 alkyl or C _1-2 alkoxy, and R ₄ is selected from the group consisting of _{C 3-8} cycloalkyl or C _{5-6 aryl.} Where C _3-8 cycloalkyl or C _5-6 aryl is substituted with one or more groups selected from hydrogen, C _1-6 alkyl, halogen and cyano, ring A is thienyl, thiazolyl, and the like. Selected from pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl or pyrazolyl, Z is selected from -CH ₂ OR _5, -COOR ₅ , -CONR ₅ R ₆ , or -NR ₅ R ₆ , where R ₅ and R ₆ are. , Independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl and C _1-6 alkyl, where R ₅ and R ₆ are substituted, the substituent is hydrogen, halogen. , Hydroxy, nitro, cyano or C _1-6 alkyl.

According to one embodiment, the present disclosure discloses compounds of formula (I) or steric isomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tally mutants, polymorphs, racemics. For mixtures, optically active compounds and pharmaceutically active derivatives, where --- is absent, X is -S-, n is 1-2 and R ₁ is C ₁ alkyl. , R ₂ and R ₃ are independently selected from hydrogen, C _1-2 alkyl or C _1-2 alkoxy, and R ₄ is selected from the group consisting of _{C 3-8} cycloalkyl or C _{5-6 aryl.} Where C _3-8 cycloalkyl or C _5-6 aryl is substituted with one or more groups selected from hydrogen, C _1-6 alkyl, halogen and cyano, ring A is thienyl, thiazolyl, and the like. Selected from pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl or pyrazolyl, Z is selected from -CH ₂ OR _5, -COOR ₅ , -CONR ₅ R ₆ , or -NR ₅ R ₆ , where R ₅ and R ₆ are. , Independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl and C _1-6 alkyl, where R ₅ and R ₆ are substituted, the substituent is hydrogen, halogen. , Hydroxy, nitro, cyano or C _1-6 alkyl.

According to other embodiments, the present disclosure describes compounds of formula (I), or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, racemates. , Racemic mixtures, optically active substances and pharmaceutically active derivatives.

Here, ---- is absent or a single bond, X is, -N -, - is selected from O- or -S-, n is 1 to 2, _{R 1} is a _{C 1} alkyl, R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl, and R ₄ is selected from the group consisting of _{C 3-8} cycloalkyl or C _{5-6 aryl, where C 3- 8} Cycloalkyl or C _5-6 aryl is substituted with one or more groups selected from hydrogen, C _1-6 alkyl, halogen and cyano, ring A is selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl. Z is selected from -CH ₂ OR _5, -COOR ₅ , -CONR ₅ R ₆ , or -NR ₅ R ₆ , where R ₅ and R ₆ are independently hydrogen or substituted or unsubstituted C _{5-. Selected from 6} aryl and C _1-6 alkyl, where R ₅ and R ₆ are substituted, the substituent is selected from hydrogen, halogen, hydroxy, nitro, cyano or C _1-6 alkyl. To.

According to other embodiments, the present disclosure describes compounds of formula (I) or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, racemates, and the like. With respect to racemic mixtures, optically active substances and pharmaceutically active derivatives.

Here, --- is absent or single bond, X is selected from -N- or -O-, n is 1-2, R ₁ is C ₁ alkyl, R ₂ and R. ₃ is independently selected from hydrogen or C _1-2 alkyl and R ₄ is selected from the group consisting of _{C 3-8} cycloalkyl or C _{5-6 aryl, where C 3-8} cycloalkyl or C _5-6 aryl is substituted with one or more groups selected from hydrogen, C _1-6 alkyl, halogen and cyano, ring A is selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl and Z is-. Chosen from CH ₂ OR _5, -COOR ₅ , -CONR ₅ R ₆ , or -NR ₅ R _{6 , R 5} and R ₆ are independently hydrogen or substituted or unsubstituted C _5-6 aryl and C. _{Selected from 1-6} alkyl, where R ₅ and R ₆ are substituted, the substituent is selected from hydrogen, halogen, hydroxy, nitro, cyano or C _1-6 alkyl.

According to one embodiment, the present disclosure describes compounds of formula (I), analogs thereof, tautomers, stereoisomers, polyforms, solvates, intermediates, pharmaceutically acceptable salts, and the like. With respect to pharmaceutical compositions, biotransforms and prodrugs.

Here, R ₁ represents a substituted or unsubstituted alkyl or cycloalkyl, X represents -O- or -N-, and A is thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, oxazolyl, triazolyl. , isoxazolyl, isothiazolyl, thiadiazolyl, represents a heteroaryl ring of 5 or 6 membered such as furyl, R ₄ represents hydrogen or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, alkyl and haloalkyl, Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , -NSO ₂ R _{6 and-} O-CO-NR ₅ represents R ₆ , R ₅ , R ₆ and R ₇ represent hydrogen or substituted or unsubstituted aryl, heteroaryl, cycloalkyl and alkyl, and n represents an integer from 0 to 6. R ₂ and R ₃ represent substituents independently selected from one or more hydrogens, halogens such as fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, azide, nitroso, oxo (= O). , Thioxo (= S), -SO _2- , amino, hydrazino, formyl, alkyl, trifluoromethyl, tribromomethyl, trichloromethyl and other haloalkyl groups, alkoxy, -OCH2Cl and other haloalkoxy, benzyloxy, phenylethoxy, etc. Arylalkoxy, Cycloalkyl, Cycloalkyloxy, Aryl, Heterocyclyl, Heteroaryl, Alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR ^a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _a C (S) R _b- , -SONR _a R _b- , -SO ₂ NR _a R _b- , -OR _{a , -OR a} C (O) OR _b- , -OC (O) NR _a R _b , OC (O) R _a , -OC (O) NR _a R _b- , _{-R a NR b R c, -R} a oR b -, - SR a, -SOR a and -SO ₂ It is selected from R _a, not limited to, wherein, R _a, R _b, and R _c in each of the above groups can be hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl and It may be an arbitrarily substituted group selected from heteroarylalkyl. Substituents are optionally further substituted with one or more substituents as defined above, and the substituents may be one or more if the _{groups R 4} , R ₅ , R ₆ and R _{7 are substituted.} Halogen such as fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), thioxo (= S), -SO _2- , amino, hydrazino, formyl, alkyl, trifluoro Haloalkyl groups such as methyl, tribromomethyl and trichloromethyl, alkoxy, haloalkoxy such as -OCH2Cl, arylalkoxy such as benzyloxy and phenylethoxy, cycloalkyl, cycloalkyloxy, aryl, heterocyclyl, heteroaryl, alkylamino,- COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR ^a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _{a C (O) R b -} , NR a C (S) R b -, - SONR a R b -, - SO 2 NR a R b -, - OR a, -OR a C (O) OR b -, _{-OC (O) NR a R b} , OC (O) R a, -OC (O) NR a R b -, - R a NR b R c, -R a OR b -, - SR a, -SOR a _and is selected from -SO ₂ R _a, not limited to, wherein, R _a in each of the above groups, _{R b} and _{R c} is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl , Heteroaryl and Heteroarylalkyl may be optionally substituted groups. Substituents are optionally further substituted by one or more substituents as defined above.

According to one embodiment, the present disclosure describes compounds of formula (I) or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemates. For mixtures, optically active compounds and pharmaceutically active derivatives, where R ₁ is methyl.

According to one embodiment, the present disclosure describes compounds of formula (I) or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemates. For mixtures, optically active compounds and pharmaceutically active derivatives, where R ₂ is hydrogen, methyl or methoxy.

According to one embodiment, the present disclosure describes compounds of formula (I) or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemates. For mixtures, optically active compounds and pharmaceutically active derivatives, where R ₃ is methyl or hydrogen.

According to one embodiment, the present disclosure describes compounds of formula (I) or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemates. mixtures relates optically active form and pharmaceutically active derivative, wherein, R ₄ is selected from C ₃ cycloalkyl or C ₆ aryl, which is unsubstituted, independently, or independently chlorine, methyl and Substituted with 3 or less substituents selected from cyano.

According to one embodiment, the present disclosure describes compounds of formula (I) or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemates. For mixtures, optically active compounds and pharmaceutically active derivatives, where X is -N-.

According to one embodiment, the present disclosure describes compounds of formula (I) or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemates. For mixtures, optically active compounds and pharmaceutically active derivatives, where X is —O—.

According to one embodiment, the present disclosure describes compounds of formula (I) or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemates. For mixtures, optically active compounds and pharmaceutically active derivatives, n is 1 or 2 here.

According to one embodiment, the present disclosure describes compounds of formula (I) or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemates. For mixtures, optically active compounds and pharmaceutically active derivatives, they are selected from the following groups.

a. ± Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine -6-yl) acetate,
b. ± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) -N-ethylacetamide,
c. (S) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N-ethylacetamide,
d. (R) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N-ethylacetamide,
e. ± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) acetamide,
f. (S) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) acetamide,
g. (R) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) acetamide,
h. ± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) -N- (4-hydroxyphenyl) acetamide,
i. (S) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N- (4-hydroxyphenyl) acetamide,
j. (R) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N- (4-hydroxyphenyl) acetamide,
k. (R) -2- (4- (4-Cyanophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-c] e] Azepine-6-yl) -N-ethylacetamide,
l. ± Ethyl 2- (4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine-6 -Il) acetate,
m. ± 2-(4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine-6- Il) -N-ethylacetamide,
n. (R) -2- (4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine -6-yl) -N-ethylacetamide,
o. (S) -2- (4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine -6-yl) -N-ethylacetamide,
p. ± Ethyl 2- (5- (4-chlorophenyl) -10-methyl-9-oxo-9,10-dihydro-7H-dipyrido [3,2-c: 3', 4'-e] azepine-7-yl ) Acetate,
q. ± Ethyl 2- (4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine -6-yl) acetate,
r. ± 2-(4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) -N-ethylacetamide,
S. ± Ethyl-2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e] Azepine-5-yl) acetate,
t. ± 2-(7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e] azepine- 5-yl) -N-ethylacetamide,
u. (S) -2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e ] Azepine-5-yl) -N-ethylacetamide,
v. (R) -2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e ] Azepine-5-yl) -N-ethylacetamide,
w. ± Ethyl 2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] azepine -6-yl) acetate,
x. ± 2-(4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] azepine- 6-yl) -N-ethylacetamide,
y. (R) -2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] ] Azepine-6-yl) -N-ethylacetamide,
z. (S) -2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] ] Azepine-6-yl) -N-ethylacetamide,
aa. ± Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4, 3-c] Pyridine-6-yl) acetate,
bb. ± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3] -C] Pyridine-6-yl) -N-ethylacetamide,
cc. 2- (4S, 6S) (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3-c] Pyridine-6-yl) -N-ethylacetamide,
dd. 2- (4R, 6R) (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3-c] Pyridine-6-yl) -N-ethylacetamide,
ee. ± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3] -C] Pyridine-6-yl) acetamide,
ff. 2-((4S, 6S) -4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] Oxepino [4,3-c] Pyridine-6-yl) acetamide,
gg. 2-((4R, 6R) -4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] Oxepino [4,3-c] Pyridine-6-yl) acetamide,
hh. ± 4- (4-chlorophenyl) -6- (2-hydroxyethyl) -2,3,9-trimethyl-4,9-dihydrothieno [2', 3': 5,6] Oxepino [4,3-c] Pyridine-8 (6H) -on,
ii. (4S, 6S) -4- (4-chlorophenyl) -6- (2-hydroxyethyl) -2,3,9-trimethyl-4,9-dihydrothieno [2', 3': 5,6] Oxepino [4] , 3-c] Pyridine-8 (6H) -on,
JJ. (4R, 6R) -4- (4-chlorophenyl) -6- (2-hydroxyethyl) -2,3,9-trimethyl-4,9-dihydrothieno [2', 3': 5,6] Oxepino [4] , 3-c] Pyridine-8 (6H) -on,
kk. ± Ethyl 2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] azepine -6-yl) acetate, and ll. ± 2-(4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-4,6,8,9-tetrahydro-3H-pyrazolo [4', 3': 5,6] oxepino [4, 3-c] Pyridine-6-yl) -N-ethylacetamide.

According to one embodiment, the present disclosure describes compounds of formula (I) or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemates. The present invention relates to a method for producing a mixture, an optically active substance and a pharmaceutically active derivative.

According to one embodiment, the present disclosure describes compounds of formula (I) or steric isomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemates. With respect to a pharmaceutical composition comprising a mixture, an optically active substance and a pharmaceutically active derivative, and at least one pharmaceutically acceptable carrier, diluent or excipient.

According to one embodiment, the present disclosure describes a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt, complex, hydrate, solvate, homozygous, polymorph, racemate. The present invention relates to a pharmaceutical composition comprising the combination of a mixture, an optically active substance and a pharmaceutically active derivative, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

According to one embodiment, the present disclosure describes compounds of formula (I) or steric isomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemics. With respect to pharmaceutical compositions containing mixtures, optically active substances and pharmaceutically active derivatives, the compositions are in the form of tablets, capsules, powders, syrups, solutions, aerosols or suspensions.

According to one embodiment, the present disclosure treats and / or prevents a disease and / or disorder having a variant, aberrant or deregulatory activity of the BET family of bromodomain-containing proteins, particularly BRD2, BRD3, BRD4 and BRDT proteins. Use of the compound of formula (I) and the compound of formula (I) or its stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, remutability in the manufacture of a pharmaceutical for With respect to the use of pharmaceutical compositions containing bodies, polyforms, racemic mixtures, optically active substances and pharmaceutically active derivatives.

According to one embodiment, the present disclosure relates to the use of a compound of formula (I) and a compound of formula (I) or a conformation thereof in the manufacture of a medicament for the production of anticancer effects in warm-blooded animals such as humans. Concerning the use of pharmaceutical compositions containing isomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active compounds and pharmaceutically active derivatives. ..

According to one embodiment, the present disclosure relates to various diseases or diseases associated with systemic or histological inflammation, inflammatory response to infection or hypoxia, cell activation and proliferation, lipid metabolism, fibrosis. With respect to methods for treatment and in the prevention and treatment of viral infections.

According to one embodiment, the present disclosure relates to a method of treating cancer in a patient, comprising administering a therapeutically effective amount of a compound of formula (I).
According to one embodiment, the present disclosure presents a therapeutically effective amount of a compound of formula (I) in the presence of other clinically relevant cytotoxic or non-cytotoxic agents in the mammal in need thereof. It relates to a method of treating a proliferative disease or cancer, which comprises administering to a subject suffering from the proliferative disease or cancer in the presence or absence.

According to one embodiment, the disclosure is caused, concomitant or accompanied by disruption of cell proliferation and / or angiogenesis and subsequent metastasis, including administration of a therapeutically effective amount of a compound of formula (I). Regarding how to treat the disorder.

According to one embodiment, the present disclosure relates to a method of treating a patient's cancer, comprising administering an effective amount of a compound of formula (I). The cancer can be either a hematological malignancy or a solid tumor. Hematological malignancies are selected from the group consisting of B-cell lymphoma, T-cell lymphoma and leukemia. In the case of solid tumors, the tumor is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, head cancer, cervical cancer, kidney cancer, gastric cancer, colon cancer, pancreatic cancer and brain cancer.

According to one embodiment, the disclosure comprises administering to a patient in need of treatment a therapeutically effective amount of a composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. It relates to a method of treating and / preventing a degenerative disease or a neurodegenerative disorder.

In one aspect of this embodiment, the invention provides a compound of formula (I) used to treat and / or prevent a neurodegenerative disease or neurodegenerative disease. In a related aspect, the invention provides the use of a compound of formula (I) for the manufacture of a neurodegenerative disease or a medicament for treating and / or preventing a neurodegenerative disease.

According to one embodiment, the present disclosure relates to compounds of formula (I) useful in the treatment of proliferative disorders. Proliferative disorders include, for example, tumor disorders and / or metastases.
According to one embodiment, the compounds of the present disclosure are for proliferative disorders that are refractory to treatment with other chemotherapeutic agents, or tumors that are refractory to treatment with other therapeutic agents due to multidrug resistance. Useful for treatment.

According to one embodiment, the disclosure comprises a method of treating cancer, comprising administering a compound or pharmaceutical composition in combination with other clinically relevant immunomodulators to a mammal in need thereof. Regarding.

According to one embodiment, the compounds of the invention slow tumor growth, arrest tumor growth, or result in tumor regression, causing tumor metastasis (including micrometastasis) and proliferation of metastasis (micrometastasis). Including) can be prevented. In addition, they may be used for epidermal hyperproliferation.

The compound of the formula (I) of the present invention may be used as a preventive agent or a therapeutic agent for cancer. Cancers include breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, neurocellular tumor, non-small cell lung cancer, small cell lung cancer, liver. Cancer, kidney cancer, bile duct cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer, hemangiomas, malignant lymphomas, malignant melanomas, thyroid cancers, bone tumors, hemangiofibroma, retinoblastoma, Examples include, but are not limited to, penile cancer, pediatric solid tumor, lymphoma, myeloma and leukemia (eg, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic neutrophil leukemia, chronic eosinophilia). Spherical leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hair cell leukemia).

The compounds of formula (I) of the present invention include rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic erythematosus, multiple sclerosis, inflammatory bowel disease (Clone's disease and ulcerative colitis), asthma, Chronic obstructive airway disease, pneumonia, myocarditis, peritonitis, myitis, eczema, dermatitis, alopecia, leukoplakia, bullous skin disease, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retina Various chronics such as inflammation, dermatitis, embolitis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, pituitary inflammation, thyroiditis, type I diabetes and acute rejection of transplanted organs It may be used as a prophylactic or therapeutic agent for autoimmune and inflammatory diseases.

In one embodiment, the present invention provides a patient in need of treatment with any amount of a composition comprising a compound of formula (I) sufficient to inhibit bromodomain activity and a pharmaceutically acceptable carrier. Provided are methods of inhibiting bromodomain activity, including administration.

In one aspect of this embodiment, the invention provides a compound of formula (I) for use in inhibiting a bromodomain. In a related aspect, the invention provides the use of a compound of formula (I) for the manufacture of a medicament for inhibiting a bromodomain.

In one embodiment, the invention comprises administering to a patient in need of treatment a therapeutically effective amount of a composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, a neurodegenerative disease or Provided are methods for treating and / or preventing neurodegenerative disorders. In one aspect of this embodiment, the invention provides a compound of formula (I) used to treat and / or prevent a neurodegenerative disease or neurodegenerative disease. In a related aspect, the invention provides the use of a compound of formula (I) in the manufacture of a neurodegenerative disease or a medicament for treating and / or preventing a neurodegenerative disease.

In other embodiments, the compounds are administered in combination therapy with compounds of formula (I) in combination with targets such as DNA methyltransferases, heat shock protein (eg, HSP90) kinases and other matrix metalloproteinases. Not limited to.

In "combination therapy", the target compound is referred to as other biologically active ingredients (eg, vinblastine, afatinib, nilotinib, vemarafinib, aflibercept, axitinib). (Axitinib), dasatinib, sorafenib, bostinib, crizotinib, but not limited to different anti-neoplastic agents) and non-pharmaceutical therapy (eg, surgery or radiotherapy, etc.) Including, but not limited to, administration in combination with (but not limited to). The compounds described herein may preferably be used in combination with other pharmaceutically active compounds that enhance the effects of the compounds of the invention. The compounds may be administered simultaneously with or in succession with other medications.

In other embodiments, the compound of interest may be used in combination with an anti-neoplastic agents that inhibit one or more biological targets (eg, small molecules, monoclonal antibodies, antisense RNA and fusion proteins). Such a combination can enhance the therapeutic efficacy beyond the efficacy achieved by either formulation alone and can prevent or delay the appearance of resistant variants.

In other embodiments, the compound of interest can be used in combination with an immunotherapeutic agent, not limited to PDL-1, IDO, TDO, CTLA4 or other formulations involved in immunomodulation.
Once described, the terms have the same meaning throughout the patent.
[scheme]
According to one embodiment, the present disclosure relates to the method set forth in Scheme 1 below for the preparation of compounds of formula (I), wherein all the groups are as defined above.

[Scheme 1]
The method for producing the compound of formula (I) includes:
Compound I was converted to Compound II under standard conditions using either malonic acid or the Wittig reagent. Compound II was treated with a boron reagent in the presence of a Pd catalyst and a suitable ligand to form Compound III. Compound V was produced by reacting Intermediate IV with Compound III in the presence of a Pd catalyst and a suitable ligand. Compound IV is used with sodium borohydride or sodium cyanoborohydride to provide the corresponding alcohol compound VI under standard carbonyl reduction. Compound VII was produced by intramolecular cyclization of compound VI with a base such as an inorganic base or an organic base. Further investigation of compound VII provides compounds of formula (I). Hydrolysis of an inorganic base such as NaOH and compound VII provides the corresponding acid compound IX, and further investigation provides the compound of formula (I). Compound V is treated with ammonium acetate in polar protic solvents such as methanol, ethanol and the like to provide compound VIII. Further investigation of compound VIII provides the compound of formula (I). Here, R ₁ , R ₂ , R ₃ , R ₄ and Z are as described above.

Compound X was converted to compound XI by treating it with a base such as n-butyllithium and DMF or an equivalent thereof. Compound XI was converted to compound XII under standard conditions using malonic acid or a whitting reagent. Compound XII was treated with a boron reagent in the presence of a Pd catalyst and a suitable ligand to form compound XIII. Compound XIII was reacted with excess methyl iodide to give compound III (Scheme 2). Further compound III is converted to formula (I) as described in Scheme 1.

The examples shown below are provided for illustration purposes only and should not be construed as limiting the scope of the invention.
[Example]
The following examples provide details about the synthesis, activity and application of the compounds of the present disclosure. It should be understood that the following examples are representative and the invention is not limited by the details described in these examples.
[Synthesis of intermediate L1]

[Preparation of 5-bromo-2-methoxyisonicotinaldehyde (1)]
A stirred solution of diisopropylamine (111.6 mL, 0.79 mol) in THF (200 mL) was cooled to −20 ° C. with dry ice acetone and slowly n-butyllithium (192 mL, 0.32 mol, 1.6 M). Was added via a cannula, stirred at the same temperature for 30 minutes and cooled to −78 ° C. 5-Bromo-2-methoxypyridine (50 g, 0.27 mol) in THF (150 mL) was added via a cannula for about 15 minutes and then stirred at the same temperature. After 1 hour, dry DMF (61.4 mL, 0.79 mol) was added, the mixture was slowly warmed to room temperature, and the mixture was stirred. After 2 hours, the reaction mixture was quenched with saturated ammonium chloride. The organic layer was dried and concentrated to give a solid. The solid was washed with cold hexanes to give 5-bromo-2-methoxyisonicotinaldehyde (40 g, 69%) as a pale yellow solid. ^{1 1} H NMR (DMSO-d ₆ , 400 MHz,) δ (ppm): 10.09 (s, 1H), 8.52 (s, 1H), 7.14 (s, 1H), 3.85 (s, 3H). MS (ESI): C ₇ H ₆ BrNO ₂ mass spectrometry 216.2, m / z, measured value 218.03 [M + H] ⁺ .
[Preparation of (E) -ethyl 3- (5-bromo-2-methoxypyridin-4-yl) acrylate (2)]
Ethyl2- (triphenylphosphoraniliden) acetate (38.6 g) in a stirred solution of methyl 5-bromo-2-methoxyisonicotinaldehyde (24 g, 0.11 mol) in dichloromethane (150 mL) cooled to 0 ° C. , 0.11 mol) was dissolved in dichloromethane (150 mL) and added dropwise. After the addition, the reaction mixture was warmed to room temperature and stirred for 10 hours, the reaction mixture was concentrated to give a residue, which was stirred with 5% ethyl acetate / hexane. The solid was filtered and the filtrate was concentrated to give (E) -ethyl 3- (5-bromo-2-methoxypyridin-4-yl) acrylate (23.6 g, 74%) as a white solid (25 g). , 95% yield). _{^{1 H NMR (DMSO-d 6}} , 400MHz,) δ (ppm): 8.40 (s, 1H), 7.68-7.64 (d, J = 16Hz, 1H), 6.90-6.87 (D, J = 16Hz, 1H), 4.25-4.19 (q, J = 24Hz, 2H), 3.84 (s, 3H), 1.28-1.24 (t, J = 16Hz, 3H). MS (ESI): _{Mass spectrometry of C 11} H ₁₂ BrNO ₃ 286.3, m / z, measured value 288.16 [M + 2H] ⁺ .
[(E) -Ethyl 3- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-4-yl) acrylate (3) ) Preparation]
Bispinaco in a stirred solution of (E) -methyl 3- (5-bromo-2-methoxypyridin-4-yl) acrylate (2,28 g, 0.098 mol) in 1,4-dioxane (500 mL). Ratodiborone (37.15 g, 0.146 mol) and potassium acetate (19.18 g, 0.195 mol) were added, degassed with nitrogen for 15 minutes, and tetrakistriphenylphosphine palladium (0) (3.4 g, 0. 005 mol) was added, and the mixture was degassed again for 5 minutes. The resulting mixture was heated at 90 ° C. for 5 hours. The reaction mixture was cooled to room temperature and filtered through a Celite layer. The filtrate was completely evaporated to give a residue, which was dissolved in 500 mL ethyl acetate and washed with water (100 mL) and brine (100 mL). The organic layer was _{dried over anhydrous Na 2} SO ₄ and filtered. The filtrate was evaporated to give a crude product. The crude product was purified by combiflash (silica gel) and eluted with 0-100% ethyl acetate in hexanes. Concentrate the pure fraction containing the required product (E) -ethyl 3- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) -Il) Pyridine-4-yl) Acrylate (24.4 g, yield 75%) was obtained. _{^{1 H NMR (DMSO-d 6}} , 400MHz,) δ (ppm): 8.57 (s, 1H), 8.37 (d, J = 15,6Hz, 1H), 6.88 (s, 1H), 6.43-6.39 (d, J = 16Hz, 1H), 4.29-4.23 (q, J = 7.6Hz, 2H), 3.9 (s, 3H), 1.34-1 .32 (t, J = 6Hz, 3H), 1.26 (s, 12H). MS (ESI): C ₁₇ H ₂₄ BNO ₅ mass spectrometry 333.1, m / z, actual measurement: 334.2 [M + H] ⁺ .
[(E) -Ethyl 3- (1-Methyl-2-oxo-5- (4, 4, 5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-dihydropyridine- 4-Il) Preparation of Acrylate (L1)]
(E) -Ethyl 3- (2-Methoxy-5- (4, 4, 5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-4-yl) in acetonitrile (14 mL) Methyl iodide (8.52 mL, 0.14 mol) was added to a stirred solution of acrylate (3, 20 g, 0.060 mol) at 0 ° C. The resulting reaction mixture was heated to 90 ° C. in a closed tube. After 12 hours, the reaction mixture was cooled to room temperature and the solvent was completely evaporated to give the crude product. The crude was purified by combiflash and eluted in hexane with 0-100% ethyl acetate. Concentrate the pure fraction containing the required product (E) -ethyl3- (1-methyl-2-oxo-5- (4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl) -1,2-dihydropyridine-4-yl) acrylate was obtained as a pale yellow solid (16 g, yield 80%). ^{1 1} H NMR (DMSO-d ₆ , 400 MHz,) δ (ppm): 8.17-8.12 (d, J = 16 Hz, 1H), 7.79 (s, 1H), 6.72 (s, 1H) ), 6.342-6.36 (d, J = 16Hz, 1H), 4.27-4.22 (q, J = 7.2Hz, 2H), 3.55 (s, 3H), 1.34 -1.31 (t, J = 7.2Hz, 3H), 1.31 (s, 12H). MS (ESI): C ₁₇ H ₂₄ BNO ₅ mass spectrometry 333.1, m / z, actual measurement: 334.2 [M + H] ⁺ .
[Synthesis of intermediate L2]

[Preparation of (2-bromo-4,5-dimethylthiophene-3-yl) (4-chlorophenyl) methanone (L2)]
A solution of (2-amino-4,5-dimethylthiophene-3-yl) (4-chlorophenyl) methanone (4, 2 g, 7.55 mmol) in acetonitrile (50 mL) was taken, cooled to 0 ° C. and tert. -Butyl nitrite (0.86 g, 8.3 mmol) was added dropwise over 10 minutes. The solution was stirred for 20 minutes, then copper (II) bromide (2.52 g, 1.13 mmol) was added and stirred at the same temperature for 1 hour. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane (50 mL) and 2N hydrochloric acid. The organic layer was separated _{, dried over anhydrous Na 2} SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by combiflash (silica gel) and eluted with 0-10% ethyl acetate / hexane. The pure fraction was concentrated to give (2-bromo-4,5-dimethylthiophene-3-yl) (4-chlorophenyl) methanone as a pink solid (0.55 g, 22%). ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 7.75 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 2.30 ( s.3H), 1.90 (s, 3H). _{MS (ESI): C 13 H} 10 BrC l O S mass calculated value 329.64, m / z, ^{Found: 331.28 [M + H] +} .
[Synthesis of intermediate L3]

[Preparation of 2-methylthiazole-4-carboxylic acid (6)]
_{EtOH: H 2 O (1:} 1,20mL) ethyl 2-methylthiazole-4-carboxylate in (5,5.0g, 29.23mmol) to a stirred solution of, NaOH at 0 to 5 ° C. (3. 58 g, 87.7 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give a solid residue. The residue was dissolved in water and acidified to about pH 5 with a 1N hydrochloric acid solution to give a pale pink solid, filtered and dried under high vacuum (3.7 g, 88% yield). MS (ESI): C ₅ H ₅ NO ₂ S mass spectrometry 143.16, m / z, measured value: 144.1 [M + H] ⁺ .
[Preparation of N-methoxy-N, 2-dimethylthiazole-4-carboxamide (7)]
DIPEA (11.67 mL, 67.05 mmol), 1- [bis (dimethylamino)) in a stirred solution of 2-methylthiazole-4-carboxylic acid (6, 3.2 g, 22.35 mmol) in dichloromethane (50 mL). Methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxo-hexafluorophosphate (HATU) (12.74 g, 33.52 mmol) was added at room temperature. The mixture was stirred for 10 minutes and N, O-dimethylhydroxylamine hydrochloride (4.36 g, 44.70 mmol) was added at 0 ° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 hours. The mixture was quenched with water. The residue was distributed in dichloromethane and water. The organic layer was washed with cold water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified with Combiflash (silica gel, 5-20% ethyl acetate / hexane) to give the product as a colorless liquid (2.6 g, 63% yield). MS (ESI): _{Mass spectrometry of C 7} H ₁₀ N ₂ O ₂ S 186.2, m / z, measured value 187.1 [M + H] ⁺ .
[Preparation of (4-chlorophenyl) (2-methylthiazole-4-yl) metanone (8)]
0 under _{N 2} atmosphere ℃ dry diethyl ether (50 mL) solution of N- methoxy -N, 2-dimethyl-4- carboxamide (7,2.6g, 13.96mmol), diethyl ether (18.14mL, A 1M solution of 4-chlorophenylmagnesium bromide in 18.14 mmol) was added dropwise. The reaction mixture was left to stir at room temperature for 16 hours. The mixture was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The reaction mixture was filtered through a Celite layer. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by Combiflash (silica gel, 5-60% ethyl acetate / hexane) to give a pale yellow solid (0.67 g, 20% yield). MS (ESI): _{Mass spectrometry of C 11} H ₈ ClNOS, 237.71, m / z, measured value: 238 [M + H] ⁺ .
[Preparation of (5-Bromo-2-methylthiazole-4-yl) (4-chlorophenyl) metanone (L3)]
N-Bromosuccinimide (1.82 g, 10.29 mmol) to (4-chlorophenyl) (2-methylthiazole-4-yl) methanone (8,0.7 g, 2.94 mmol) in acetonitrile (10 mL) at room temperature. added. The reaction mixture was stirred at 80 ° C. for 12 hours. The mixture was quenched with water. The residue was distributed in ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified with Combiflash (silica gel, 5-20% ethyl acetate / hexane) to give the product as a brown solid (0.29 g, 31.5% yield). MS (ESI): C ₁₁ H ₇ BrClNOS mass spectrometric value 316.61, m / z, measured value: 315.19 [M-1] ⁻ .
Synthesis of intermediate L4

[Preparation of 2-bromo-N-methoxy-N-methylnicotinamide (11)]
DIPEA (8.6 mL, 49.5 mmol), N-[(dimethylamino) -1H-1) in a stirred solution of 2-bromonicotinic acid (9,5.0 g, 20.3 mmol) in dry dichloromethane (150 mL). , 2,3-Triazolo- [4,5-b] Pyridine-1-ylmethylene] -N-Ethylmethane Aminium Hexafluorophosphate N-Oxide (HATU) (12.2 g, 32.1 mmol) and N, O -Dimethylhydroxylamine hydrochloride (10, 3.14 g, 32.1 mmol) was added at 0 ° C. under an N2 atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified with Combiflash (silica gel, 15-25% ethyl acetate / hexane) to give the product as a white solid (5.1 g, 83.0% yield). MS (ESI): _{Mass spectrometry of C 10} H ₁₁ BrNO ₃ , 245.11, m / z, measured value: 246.9 [M + H] ⁺ .
[Preparation of (2-bromopyridin-3-yl) (4-chlorophenyl) methanone (L4)]
Diethyl ether (23 mL, 22) in a stirred solution of 2-bromo-N-methoxy-N-methylnicotinamide (11, 5.0 g, 20.3 mmol) in dry THF (100 mL) under _{an N 2} atmosphere at 0 ° C. A solution of 1.0 M4-chlorophenylmagnesium bromide in (0.4 mmol) was added dropwise. The reaction mixture was stirred for 3 hours, the reaction mixture was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The reaction mixture was filtered through a Celite layer. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the product as a grayish white solid (5.0 g, 82% yield). MS (ESI): C ₁₂ H ₇ BrClNO mass spectrometry, 294.5, m / z, measured value: 295.9 [M + H] ⁻ .
[Synthesis of intermediate L5]

[Preparation of 2-cyclopropyl-N-methoxy-N-methylacetamide (13)]
HATU (5 g, 15.0 mmol) was added to a solution of 2-cyclopropyl acetate (12, 1.0 g, 10.0 mmol) in DMF (5 mL), stirred for 5 minutes, and then diisopropylamine (11.5 mL, 70). After adding (0.0 mmol), N, O-dimethylhydroxylamine hydrochloride (4.87 g, 50.0 mmol) was added. After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with water and brine solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by combiflash (silica gel) and eluted with 0-15% ethyl acetate in hexanes. The pure fraction was concentrated to give 2-cyclopropyl-N-methoxy-N-methylacetamide (1.2 g, 85% yield) as a white solid. ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 3.60 (s, 3H), 3.05 (s, 3H), 2.26 (d, J = 8 Hz, 2H), 0.93 -0.91 (m, 1H), 0.42-0.40 (m, 2H), 0.09-0.07 (m, 2H). MS (ESI): _{Mass spectrometry of C 7} H ₁₃ NO ₂ , 143.09, m / z, measured value: 144.1 [M + H].
[Preparation of 4-cyclopropyl-3-oxobutanenitrile (14)]
To a solution of acetonitrile (3.4 mL, 66.0 mmol) in THF (30 mL) was added n-butyllithium (33 mL, 52.0 mmol) at −78 ° C. and stirred for 45 minutes. 2-Cyclopropyl-N-methoxy-N-methylacetamide (13, 6.3 g, 44.0 mmol) was then dissolved in THF (5 mL), added slowly and stirred at −78 ° C. After 1 hour, the mixture was slowly warmed to 25 ° C. and stirred. After 2 hours, the reaction mixture was quenched with saturated ammonium chloride solution. The organic layer was separated _{, dried over anhydrous Na 2} SO ₄ , filtered and concentrated to give a residue. The crude product was purified by combiflash (silica gel) and eluted with 0-20% ethyl acetate / hexane. The pure fraction was concentrated to give a 4-cyclopropyl-3-oxobutanenitrile (5.5 g, 98% yield) white solid. ^{1 1} HNMR: (400 MHz, CDCl ₃ ) δ (ppm): 3.51 (s, 2H), 2.48 (d, J = 8 Hz, 2H), 1.03-0.97 (m, 1H), 0 .66-0.61 (m, 2H), 0.20-0.15 (m, 2H). MS (ESI): _{Mass spectrometry of C 7} H ₉ NO, 123.07, m / z, measured value: 124.1 [M + H].
[Preparation of 1- (2-amino-4,5-dimethylthiophene-3-yl) -2-cyclopropylethane-1-one (15)]
4-Cyclopropyl-3-oxobutanenitrile (14, 5.5 g, 44.7 mmol), 2-butanone (3.2 g, 44.7 mmol) and morpholine (3.8 mL, 44.7 mmol) in ethanol (150 mL). ), Sulfur (1.4 g, 6.9 mmol) was added as a solid at 25 ° C. The mixture was then heated to 70 ° C. After 12 hours, the reaction mixture is cooled to 25 ° C. and poured into brine (100 mL). The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on combiflash (silica gel) and eluted with 0-20% ethyl acetate / hexane. The pure fraction is concentrated to give a yellow solid of 1- (2-amino-4,5-dimethylthiophene-3-yl) -2-cyclopropylethane-1-one (6.3 g, 67% yield). Obtained. ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.03 (bs, 2H), 2.59 (d, J = 8 Hz, 2H), 2.10 (s, 3H) 2.05 ( s, 3H), 1.01-0.98 (m, 1H), 0.44-0.39 (m, 2H), 0.09-0.05 (m, 2H). MS (ESI): C ₁₁ H ₁₅ NOS mass spectrometry, 209.13, m / z, measured value: 210.1 [M + H].
[Preparation of 1- (2-bromo-4,5-dimethylthiophene-3-yl) -2-cyclopropylethane-1-one (L5)]
A solution of 1- (2-amino-4,5-dimethylthiophene-3-yl) -2-cyclopropylethane-1-one (15, 1.3 g, 6.22 mmol) in acetonitrile (30 mL) was taken. , Cooled to 0 ° C., and tert-butyl nitrite (0.83 g, 8.08 mmol) was added dropwise over 10 minutes. The solution was stirred for 20 minutes, then copper (II) bromide (2.08 g, 9.33 mmol) was added and stirred at the same temperature for 1 hour. After 1 hour, the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was then diluted with DCM (50 mL) and 2NHCl. The organic layer was separated _{, dried over anhydrous Na 2} SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by combiflash and eluted with 0-10% ethyl acetate / hexane. The pure fraction is concentrated to add 1- (2-bromo-4,5-dimethylthiophene-3-yl) -2-cyclopropylethane-1-one (0.81 g, 47% yield) in orange. Obtained as a solid. ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 2.74 (d, J = 8 Hz, 2H), 2.24 (s, 3H), 2.04 (s, 3H), 1.01 -0.98 (m, 1H), 0.48-0.44 (m, 2H), 0.13-0.09 (m, 2H). MS (ESI): _{Mass spectrometry of C 11} H ₁₃ BrOS, 273.19, m / z, measured value: 275.1 [M + 2].
[(4-Chlorophenyl) (1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-5-yl) methanone-L6 Synthesis]

[Preparation of 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (17)]
To a stirred solution of 1-methyl-1H-pyrazole-5-carbaldehyde (5.00 g, 0.045 mol) in DMF (40 mL), add the NBS solution (8.1 g, 0.045 mol) in DMF at 0 ° C. It was added slowly over 10 minutes. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was confirmed by TLC, icebreaker was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the organic moiety was concentrated. Purification was carried out with combiflash (silica gel: ethyl acetate / hexane), and the target compound was eluted with pure hexane. Column fractions containing the required spots were collected and evaporated to give 99.58% pure 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (6.5 g, 76% yield). .. MS (ESI): Mass spectrometry of _{C 5} H _{5 BrN 2} O, 187.96, m / z, measured value: 189.0 [M + H] ⁺ .
[Preparation of (4-Bromo-1-methyl-1H-pyrazole-5-yl) (4-chlorophenyl) methanol (18)]
In a stirred solution of 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (6.00 g, 0.032 mol) in THF (40 mL), in diethyl ether (1.3 mL, 0.0415 mol) ( A 1.0 M solution of 4-chlorophenyl) magnesium bromide was added slowly at 0 ° C. over 10 minutes. The reaction mixture was stirred at 0 ° C. for 30 minutes, followed by room temperature for 1 hour. After completion of the reaction, the mixture was confirmed by TLC, icebreaker was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the organic moiety was concentrated. Purification was carried out by n-pentane washing to obtain 70% pure (4-bromo-1-methyl-1H-pyrazole-5-yl) (4-chlorophenyl) methanol (10.0 g, quantitative). MS (ESI): _{Mass spectrometry of C 11} H ₁₀ BrClN ₂ O, 299.97, m / z, measured value: 311.0 [M + H] ²⁺ .
[Preparation of (4-Bromo-1-methyl-1H-pyrazole-5-yl) (4-chlorophenyl) metanone (19)]
Pyridinium chlorochromate (10.) In a stirred solution of (4-bromo-1-methyl-1H-pyrazole-5-yl) (4-chlorophenyl) methanol (10.0 g, 0.033 mol) in DCM (40 mL). 0 g, 0.0462 mol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was confirmed by TLC. Saturated NaHCO ₃ solution was added and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the organic moiety was concentrated. Purification was performed with combiflash (silica gel: ethyl acetate / hexane) and the desired compound was eluted with 4% EA / hexane. Column fractions containing the required spots were collected and evaporated to give (4-bromo-1-methyl-1H-pyrazole-5-yl) (4-chlorophenyl) methanone to a purity of 98.85% (7. 0 g, yield 70%). MS (ESI): _{Mass spectrometry of C 11} H ₈ BrClN ₂ O, 297.95, m / z, measured value: 299.0 [M + H] ⁺ .
[(4-Chlorophenyl) (1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-5-yl) metanone (L6) Preparation]
Bis (pinacolato) in a stirred solution of (4-bromo-1-methyl-1H-pyrazole-5-yl) (4-chlorophenyl) methanone (10.0 g, 0.035 mol) in 1,4-dioxane (100 mL). ) Diborane (15.18 g, 0.04385 mol) and potassium acetate (23.58 g, 0.28 mol) were added, and degassing was performed for 20 minutes. Then, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) catalyst (2.4 g, 0.0070 mol) was added, and the mixture was further degassed. The reaction mixture was refluxed for 4 hours. After completion of the reaction, it was confirmed by TLC, filtered, and the reaction mixture was concentrated. The residue was dissolved in EA, washed with water and brine, dried over anhydrous sodium sulfate, and the organic moiety was concentrated. Purification was performed with combiflash (silica gel: ethyl acetate / hexane) and the desired compound was eluted with 60% EA / hexane. The column fraction containing the required spots was collected, evaporated and in 81.45% purity (4-chlorophenyl) (1-methyl-4- (4,4,5,5-tetramethyl-1,3,2). -Dioxaborolan-2-yl) -1H-pyrazole-5-yl) methanone was obtained (4.5 g, yield 38%). MS (ESI): C ₁₇ H ₂₀ BClN ₂ O ₃ mass spectrometry, 346.13, m / z, actual measurement: 347.1 [M + H] ⁺ .
[Example 1]
± Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine -6-yl) acetate

(E) -Ethyl 3- (5- (3- (4-chlorobenzoyl) -4,5-dimethylthiophen-2-yl) -1-methyl-2-oxo-1,2-dihydropyridine-4-yl) Preparation of Acrylate (20) (2-Bromo-4,5-Dimethylthiophene-3-yl) (4-chlorophenyl) Methylanone (Intermediate L2, 0.5 g, 1.5 mmol), (E) -Ethyl 3 -(1-Methyl-2-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-dihydropyridine-4-yl) acrylate A mixture of (Intermediate L1, 0.61 g, 1.80 mmol) and 2M aqueous sodium bicarbonate solution (0.25 g, 3.00 mmol) was added to toluene (20 mL). The mixture was purged with nitrogen gas for 10 minutes. Next, tetrakis (triphenylphosphine) palladium (0) (0.173 g, 0.15 mmol) was added, nitrogen gas was purged again for 5 minutes, and the mixture was heated at 105 ° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by combiflash and eluted with 0-10% methanol in dichloromethane. The pure fraction is concentrated to (E) -ethyl 3-(5- (3- (4-chlorobenzoyl) -4,5-dimethylthiophen-2-yl) -1-methyl-2-oxo-1. , 2-Dihydropyridine-4-yl) acrylate (0.45 g, 65.2%) was obtained as a pale pink rubbery substance. ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 7.684 (s, 1H), 7.53 (d, J = 12 Hz, d), 7.41 (d, J = 12 Hz, 2H) , 7.11 (d, J = 16Hz, 1H) 6.57 (s, 1H), 6.39 (d, J = 16Hz, 1H), 4.10 (q, J = 8Hz, 2H), 3. 32 (s, 3H), 2.39 (s, 3H), 1.99 (s, 3H), 0.83 (t, J = 8Hz, 3H). MS (ESI): Mass spectrometry of _{C 24} H _{22 ClNO 4} S, 455.10, m / z, measured value: 456.0, [M + H] ⁻ .
[± Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e]] Preparation of azepine-6-yl) acetate]
(E) -Ethyl 3- (5- (3- (4-chlorobenzoyl) -4,5-dimethylthiophen-2-yl) -1-methyl-2-oxo-1,2-) in ethanol (12 mL) Ammonium formate (1.7 g, 27.0 mmol) was added to a solution of dihydropyridine-4-yl) acrylate (20, 0.63 g, 0.14 mmol) and heated to 90 ° C. After 24 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a residue. The crude was purified by combiflash and eluted with 0-10% methanol in dichloromethane. The pure fraction was concentrated to give the product (0.47 g, 74%) as a pale yellow solid. ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.05 (s, 1H), 7.44 (d, J = 8.4 Hz, 2H) 7.29 (d, J = 8.4 Hz) , 2H) 6.39 (d, J = 16Hz, 1H) 4.25-4.21 (m, 1H), 4.15 (q, J = 4Hz, 2H), 3.46 (s, 3H), 3.26 (d, J = 8Hz, 1H) 3.16 (d, J = 8Hz, 1H), 2.36 (s, 3H), 1.59 (s, 3H), 0.85 (t, J) = 8Hz, 3H). MS (ESI): C ₂₄ H ₂₃ ClN ₂ O ₃ S mass spectrometry 454.11, m / z, actual measurement: 455.1 [M + H] ⁻ .
[2- (4- (4-Chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- Preparation of 6-yl) acetic acid (21)]
Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-c] in methanol (30 mL) A 4N sodium hydroxide solution (3.62 g, 90.6 mmol) was added to a solution of 3-e] azepine-6-yl acetate, and the solution was stirred at room temperature. After 5 hours, the mixture was concentrated to remove volatiles to give a residue, which was taken in water and acidified with 2N HCl to give a solid. The solid is filtered and dried to give 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [ 2,3-e] Azepine-6-yl) acetic acid (1.65 g, yield 85%) was obtained as a pale yellow solid. ^{1 1} H NMR: (400 MHz, DMSO) δ (ppm): 12.29 (s, 1H), 8.04 (s, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.16 (D, J = 8.0Hz, 2H), 6.37 (s, 1H), 4.24 (t, J = 8Hz, 1H), 3.45 (s, 3H), 3.11-3.15 (M, 2H), 2.36 (s, 3H), 1.59 (s, 3H). MS (ESI): Mass spectrometry of _{C 22} H _{19 ClN 2} O ₃ S, 426.08, m / z, measured value: 427.2 [M + H].
[Example 2]
± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) -N-ethylacetamide

Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- A solution of 6-yl) acetate (Example 1, 0.4 g, 0.88 mmol) ethylamine (2.1 mL, 2 M solution in THF) was cooled to 0 ° C. and trimethylaluminum (2.1 mL, in THF). 2M solution) was added. After 30 minutes, the mixture was warmed to room temperature and then heated at 80 ° C. After 1 hour, the reaction mixture was cooled to room temperature, the mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by combiflash and eluted with 0-10% methanol in dichloromethane. Concentrate the pure fraction to 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [4,3-c] 2,3-e] Azepine-6-yl) -N-ethylacetamide was obtained as a pale yellow solid (0.14 g, 35%). ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.12 (bs, 1H), 8.02 (s, 1H), 7.43 (d, J = 8 Hz, 2H), 7.32 (D, J = 8Hz, 2H), 6.41 (s, 1H), 4.26 (t, J = 8Hz, 1H), 3.45 (s, 3H), 3.10-3.04 (m) , 2H), 2.96-2.94 (m, 2H), 2.36 (s, 3H), 1.59 (s, 3H), 1.01 (t, J = 8Hz, 3H). MS (ESI): C ₂₄ H ₂₄ ClN ₃ O ₂ S mass spectrometry, 453.13, m / z, measured value: 454.2 [M + H] ⁺ .
[Preparative chiral HPLC method for separation of enantiomers 2a and 2b]

Preparative chiral HPLC method for separation of enantiomers:
Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm)
Monitoring wavelength 225 nm
Mobile phase: 100% MeOH
[Example 2a]
(S) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N-ethylacetamide.

^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.12 (bs, 1H), 8.02 (s, 1H), 7.43 (d, J = 8 Hz, 2H), 7.32 (D, J = 8Hz, 2H) 6.41 (s, 1H) 4.26 (t, J = 8Hz, 1H) 3.45 (s, 3H) 3.10-3.04 (m, 2H) 2 .96-2.94 (m, 2H) 2.36 (s, 3H) 1.59 (s, 3H) 1.01 (t, J = 8Hz, 3H). MS (ESI): C ₂₄ H ₂₄ ClN ₃ O ₂ S mass spectrometry, 453.13, m / z, measured value: 454.2 [M + H] ⁺ .
[Example 2b]
(R) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N-ethylacetamide
^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.12 (bs, 1H), 8.02 (s, 1H), 7.43 (d, J = 8 Hz, 2H) 7.32 ( d, J = 8Hz, 2H) 6.41 (s, 1H) 4.26 (t, J = 8Hz, 1H) 3.45 (s, 3H) 3.10-3.04 (m, 2H) 2. 96-2.94 (m, 2H) 2.36 (s, 3H) 1.59 (s, 3H) 1.01 (t, J = 8Hz, 3H). MS (ESI): C ₂₄ H ₂₄ ClN ₃ O ₂ S mass spectrometry, 453.13, m / z, measured value: 454.2 [M + H] ⁺ .
[Example 3]
± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) acetamide

2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] in DMF (5 mL)] HATU (0.26 g, 0.699 mmol) was added to a solution of oxepino [4,3-c] pyridine-6-yl) acetic acid (21, 0.2 g, 0.47 mmol), and the mixture was stirred for 5 minutes and then aqueous ammonia (21, 0.2 g, 0.47 mmol). 7 mL) was added. After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with water and brine solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a residue. The crude product was purified by combiflash and eluted with 0-10% MeOH / DCM. Concentrate the pure fraction to 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5 , 6] Oxepino [4,3-c] pyridin-6-yl) acetamide (145 mg, 56% yield) was obtained as an off-white solid. _{^{1 H NMR (DMSO-d 6}} , 400MHz) δ (ppm): 8.02 (s, 1H), 7.59 (s, 1H), 7.43 (d, J = 8Hz, 2H) 7.33 ( d, J = 8.0Hz, 2H) 6.89 (s, 1H) 6.41 (s, 1H) 4.26 (t, J = 4Hz, 1H) 3.45 (s, 3H) 3.01- 2.91 (m, 2H) 2.36 (s, 3H) 1.59 (s, 3H). MS (ESI): Mass spectrometry of _{C 22} H _{20 ClN 3} O ₂ S, 428.10, m / z, measured value: 429.1 [M + 1].
[Preparative chiral HPLC method for separation of enantiomers 3a and 3b]

Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm)
Monitoring wavelength 265 nm
Mobile phase: 0.1% DEA in 100% MeOH
[Example 3a]
(S) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) acetamide
^{1 1} H NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.02 (s, 1H), 7.59 (s, 1H), 7.43 (d, J = 8Hz, 2H), 7.33 (D, J = 8.0Hz, 2H), 6.89 (s, 1H), 6.41 (s, 1H), 4.26 (t, J = 4Hz, 1H), 3.45 (s, 3H) ), 3.01-2.91 (m, 2H), 2.36 (s, 3H), 1.59 (s, 3H). MS (ESI): Mass spectrometry of _{C 22} H _{20 ClN 3} O ₂ S, 428.10, m / z, measured value: 429.1 [M + 1].
[Example 3b]
(R) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) acetamide
^{1 1} H NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.02 (s, 1H), 7.59 (s, 1H), 7.43 (d, J = 8Hz, 2H), 7.33 (D, J = 8.0Hz, 2H), 6.89 (s, 1H), 6.41 (s, 1H), 4.26 (t, J = 4Hz, 1H), 3.45 (s, 3H) ), 3.01-2.91 (m, 2H), 2.36 (s, 3H), 1.59 (s, 3H). MS (ESI): Mass spectrometry of _{C 22} H _{20 ClN 3} O ₂ S, 428.10, m / z, measured value: 429.1 [M + 1].
[Example 4]
± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) -N- (4-hydroxyphenyl) acetamide

Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- A solution of 6-yl) acetate (Example 1, 0.35 g, 0.76 mmol) and 4-aminophenol (0.41 g, 0.76 mmol) was taken in THF (3 mL), cooled to 0 ° C. and trimethyl. Aluminum (1.81 mL, 2M solution in THF) was added. After 30 minutes, the mixture was warmed to room temperature and then heated at 80 ° C. After 1 hour, the reaction mixture was cooled to room temperature, the mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by combiflash and eluted with 0-10% methanol in dichloromethane. Concentrate the pure fraction to 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [4,3-c] 2,3-e] Azepine-6-yl) -N- (4-hydroxyphenyl) acetamide (0.161 g, 41%) was obtained as a pale yellow solid. ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 9.94 (s, 1H), 9.12 (s, 1H), 8.04 (bs, 1H), 7.42 (d, J) = 8Hz, 2H), 7.34-7.30 (m, 4H), 6.66 (d, J = 8.4Hz, 2H), 6.47 (s, 1H), 4.34 (t, J) = 4Hz, 1H), 3.45 (s, 3H), 3.18-3.16 (m, 2H), 2.36 (s, 3H) 1.59 (s, 3H). MS (ESI): Mass spectrometry of _{C 28} H _{24 ClN 3} O ₃ S, 517.2, m / z, measured value: 518.1 [M + H] ⁺ .

[Preparative chiral HPLC method for separation of enantiomers of Example 4]
CHIRALPAK IA (250 mm x 4.6 mm x 5 μm)
Monitoring wavelength is 254 nm
Mobile phase: 0.1% DEA in 100% MeOH
[Example 4a]
(S) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N- (4-hydroxyphenyl) acetamide
^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 9.94 (s, 1H), 9.12 (s, 1H), 8.04 (bs, 1H), 7.42 (d, J) = 8Hz, 2H), 7.34-7.30 (m, 4H), 6.66 (d, J = 8.4Hz, 2H), 6.47 (s, 1H), 4.34 (t, J) = 4Hz, 1H), 3.45 (s, 3H), 3.18-3.16 (m, 2H), 2.36 (s, 3H) 1.59 (s, 3H). MS (ESI): Mass spectrometry of _{C 28} H _{24 ClN 3} O ₃ S, 517.2, m / z, measured value: 518.1 [M + H] ⁺ .
[Example 4b]
(R) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N- (4-hydroxyphenyl) acetamide
^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 9.94 (s, 1H), 9.12 (s, 1H), 8.04 (bs, 1H), 7.42 (d, J) = 8Hz, 2H), 7.34-7.30 (m, 4H), 6.66 (d, J = 8.4Hz, 2H), 6.47 (s, 1H), 4.34 (t, J) = 4Hz, 1H), 3.45 (s, 3H), 3.18-3.16 (m, 2H), 2.36 (s, 3H) 1.59 (s, 3H). MS (ESI): Mass spectrometry of _{C 28} H _{24 ClN 3} O ₃ S, 517.2, m / z, measured value: 518.1 [M + H] ⁺ .
[Example 5]
(R) -2- (4- (4-Cyanophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-c] e] Azepine-6-yl) -N-ethylacetamide.

(R) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno in DMF (2 mL) _{[2,3-e] Zn (CN) 2} (0.04 g, 0.33 mmol) in a stirred solution of azepine-6-yl) -N-ethylacetamide (0.1 g, 0.22 mmol, Example 2a). The reaction mixture was purged with nitrogen gas for 15 minutes. Dppf (12 mg, 0.02 mmol) and Pd ₂ (dba) ₃ (10 mg, 0.01 mmol) were added to the reaction mixture. The reaction mixture was heated in a closed tube at 130 ° C. for 16 hours. The mixture was quenched with water and concentrated to remove DMF. 5% MeOH in DCM was added to the residue. The organic layer containing the product was washed with cold water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The crude product was depurified by combiflash (eluted with 1-5% MeOH / DCM) to give a white solid (0.018 g, 40% yield). _{^{1 H-NMR (DMSO-d}} 6, 400MHz) δ (ppm): 8.13 (t, 1H), 8.04 (s, 1H), 7.43 (d, J = 8.4Hz, 2H), 7.47 (d, J = 8.4Hz, 2H), 6.42 (s, 1H), 4.3 (t, J = 7.6Hz, 1H), 3.45 (s, 3H), 3. 11-3.04 (m, 2H), 2.98-2.96 (m, 2H), 2.36 (s, 3H), 1.56 (s, 3H), 1.01 (t, J = 7.6Hz, 3H). MS (ESI): C ₂₅ H ₂₄ N ₄ O ₂ S mass spectrometry, 444.56, m / z, measured value: 445.1 [M + H] ⁺ .
[Example 6]
± Ethyl 2- (4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine-6 -Il) acetate

[(E) -Ethyl 3- (5- (4- (4-chlorobenzoyl) -2-methylthiazole-5-yl) -1-methyl-2-oxo-1,2-dihydropyridine-4-yl) acrylic Preparation of acid salt (22)]
(E) -Ethyl 3 in a stirred solution of (5-bromo-2-methylthiazole-4-yl) (4-chlorophenyl) metanone (intermediate L3, 0.24 g, 0.75 mmol) in toluene (3 mL). -(1-Methyl-2-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-dihydropyridine-4-yl) acrylate (Intermediate L1, 0.33 g, 0.99 mmol) was added, 2N sodium bicarbonate (0.76 mL, 1.52 mmol) was added at room temperature, purged with nitrogen gas for 15 minutes, followed by Pd (PPh ₃ ) ₄ (0.087 g, 0.075 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 110 ° C. for 12 hours. The reaction mixture was cooled to room temperature and the mixture was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified with Combiflash (silica gel, 5-60% ethyl acetate / hexane) to give a brown solid (0.18 g, 53% yield). MS (ESI): C ₂₂ H ₁₉ ClN ₂ O ₄ S mass spectrometry, 442.92, m / z, measured value: 443.1 [M + H] ⁺ .
[Example 6]
± Ethyl 2- (4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine-6 -Il) Acetate (E) -Ethyl 3- (5- (4- (4-Chlorobenzoyl) -2-methylthiazole-5-yl) -1-methyl-2-oxo-1) in EtOH (4 mL) Ammonium formate (1.03 mL, 16.28 mmol) was added to a stirred solution of 2-dihydropyridine-4-yl) acrylate (22, 0.18 g, 0.4 mmol) at room temperature. The mixture was stirred at 85 ° C. for 18 hours. The reaction mixture was concentrated to give a solid residue. The residue was dissolved in water, extracted twice with 10% MeOH / dichloromethane, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified with Combiflash (silica gel, 2-4% MeOH / dichloromethane) to give the product as an off-white solid. ^{1 1} H NMR (DMSO-d ₆ , 400 MHz,) δ (ppm): 8.16 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8) .4Hz, 2H), 6.43 (s, 1H), 4.29-4.26 (t, J = 4.4Hz, 1H), 4.1-4.07 (m, 2H), 3.46 (S, 3H), 3.38-3.33 (s, 3H), 3.12 (m, 2H), 1.18-1.15 (t, J = 10.4Hz, 3H). MS (ESI): Mass spectrometry of _{C 22} H _{20 ClN 3} O ₃ S, 441.94, m / z, measured value: 442.0 [M + H] ⁺ .
[Example 7]
± 2-(4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine-6- Il) -N-Ethylacetamide Ethyl2- (4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3] in dry dry THF (100 mL) -C] Ethylamine (0.45 mL, 0.9 mmol, THF solution) in a stirring solution of thiazolo [5,4-e] azepine-6-yl) acetate (Example 6, 0.05 g, 0.113 mmol). , Subsequently, trimethylaluminum (0.45 mL, 0.9 mmol) was added at 0 ° C. The mixture was stirred at 90 ° C. for 6 hours. The mixture was quenched with saturated ammonium chloride. The residue was distributed in ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified in a combiflash purifier using 2-3% MeOH / dichloromethane to give the product as an off-white solid (0.02 g, 40% yield). ^{1 1} H NMR (DMSO-d ₆ , 400 MHz,) δ (ppm): 8.14 (bs, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8) .4Hz, 2H), 6.42 (s, 1H), 4.3 (t, J = 6Hz, 1H), 3.45 (s, 3H),), 3.14-3.02 (m, 3H) ), 2.94-2.9 (m, 1H), 2.7 (s, 3H), 1.01 (t, J = 7.2Hz, 3H). MS (ESI): C ₂₂ H ₂₁ ClN ₄ O ₂ S mass spectrometry, 440.96, m / z, measured value: 441.1.
[Preparative chiral HPLC method for separation of enantiomers of Example 7]
CHIRALPAK IA (250 mm x 4.6 mm x 5 μm)
Monitoring wavelength: 254 nm
Mobile phase: 0.1% DEA in 100% MeOH

[Example 7a]
(R) -2- (4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine -6-yl) -N-ethylacetamide 1H NMR (DMSO-d ₆ , 400 MHz,) δ (ppm): 8.14 (bs, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.4Hz, 2H), 6.42 (s, 1H), 4.3 (t, J = 6Hz, 1H), 3.45 (s, 3H),), 3. 14-3.02 (m, 3H), 2.94-2.90 (m, 1H), 2.7 (s, 3H), 1.01 (t, J = 7.2Hz, 3H). MS (ESI): C ₂₂ H ₂₁ ClN ₄ O ₂ S mass spectrometry, 440.96, m / z, measured value: 441.1.
[Example 7b]
(S) -2- (4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine -6-yl) -N-ethylacetamide 1H NMR (DMSO-d ₆ , 400 MHz,) δ (ppm): 8.14 (bs, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.4Hz, 2H), 6.42 (s, 1H), 4.3 (t, J = 6Hz, 1H), 3.45 (s, 3H),), 3. 14-3.02 (m, 3H), 2.94-2.90 (m, 1H), 2.7 (s, 3H), 1.01 (t, J = 7.2Hz, 3H). MS (ESI): C ₂₂ H ₂₁ ClN ₄ O ₂ S mass spectrometry, 440.96, m / z, measured value: 441.1.
[Example 8]
± Ethyl 2- (5- (4-chlorophenyl) -10-methyl-9-oxo-9,10-dihydro-7H-dipyrido [3,2-c: 3', 4'-e] azepine-7-yl ) Acetate

[(E) -Ethyl 3- (3- (4-chlorobenzoyl) -1'-methyl-6'-oxo-1', 6'-dihydro- [2,3'-bipyridine] -4'-yl) Preparation of acrylate (23)]
(E) -Ethyl in a stirred solution of (2-bromopyridin-3-yl) (4-chlorophenyl) methanone (intermediate L4, 0.5 g, 1.5 mmol) in dimethoxyethane / water (60: 15 mL) 3- (1-Methyl-2-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-dihydropyridin-4-yl) acrylic acid Salt (intermediate L1, 0.45 g, 1.5 mmol) and sodium carbonate (0.5 g, 4.5 mmol) were added at room temperature, purged with nitrogen gas for 15 minutes, followed by Pd (PPh ₃ ) ₄ (0. 2 g, 0.15 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 90 ° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was distributed in ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified with Combiflash (silica gel, 60-70% ethyl acetate / hexane) to give about 50% product. MS (ESI): Mass spectrometry of _{C 23} H _{19 ClN 2} O ₄ , 422.8, m / z, measured value: 423 [M + H] ⁺ .
[Example 8]
± Ethyl 2- (5- (4-chlorophenyl) -10-methyl-9-oxo-9,10-dihydro-7H-dipyrido [3,2-c: 3', 4'-e] azepine-7-yl ) Acetate EtOH (4 mL) (E) -Ethyl 3- (3- (4-chlorobenzoyl) -1'-methyl-6'-oxo-1', 6'-dihydro- [2,3'- Ammonium formate (5.0 g, 32 mmol) was added to a stirred solution of bipyridine] -4'-yl) acrylate (23.3 g, 0.71 mmol) at room temperature. The mixture was stirred in an autoclave vessel at 85 ° C. for 18 hours. The reaction mixture was concentrated to give a solid residue. The residue was dissolved in water, extracted twice with 10% MeOH / dichloromethane, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified with Combiflash (silica gel, 2-4% MeOH / dichloromethane) to give a 40% product. MS (ESI): Mass spectrometry of _{C 23} H _{20 ClN 3} O ₃ , 421.92, m / z, measured value: 424.0 [M + H] ⁺ .
[Example 9]
± Ethyl 2- (4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine -6-yl) acetate

[Ethyl (E) -3- (5- (3- (2-cyclopropylacetyl) -4,5-dimethylthiophen-2-yl) -1-methyl-2-oxo-1,2-dihydropyridine-4- Il) Preparation of acrylate (24)]
1- (2-Bromo-4,5-dimethylthiophene-3-yl) -2-cyclopropylethane-1-one (0.8 g, 2.93 mmol, L5), ethyl (E) -3- (1-) Methyl-2-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-dihydropyridine-4-yl) acrylate (L1,1) A mixture of .17 g, 3.51 mmol) and 2M sodium bicarbonate (0.98 g, 11.72 mmol) was mixed in toluene (30 mL). The mixture was purged with nitrogen gas for 10 minutes. Tetrakis (triphenylphosphine) palladium (0) (0.68 g, 0.58 mmol) was then added to the mixture and nitrogen gas was purged through the mixture for 5 minutes. The mixture was heated to 105 ° C. and after 15 hours the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to give a residue. The crude was purified by combiflash and eluted with 0-10% MeOH / DCM. The pure fraction is concentrated to (E) -3- (5- (3- (2-cyclopropylacetyl) -4,5-dimethylthiophen-2-yl) -1-methyl-2-oxo-1. , 2-Dihydropyridine-4-yl) acrylate (0.42 g, 36% yield) was obtained as a pale pink liquid. ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 7.89 (s, 1H), 7.22 (d, J = 36 Hz, 1H), 6.85 (s, 1H), 6.59 (D, J = 16Hz, 1H), 4.11 (q, J = 8Hz, 2H), 3.42 (s, 3H), 2.32 (s, 3H), 2.25 (d, J = 8Hz) , 2H), 2.08 (s, 3H), 1.24 (t, J = 8Hz, 3H), 0.78 (m, 1H), 0.36-0.31 (m, 2H), 0. 16-0.14 (m, 2H). MS (ESI): _{Mass spectrometry of C 22} H ₂₅ NO ₄ S, 399.15, m / z, measured value: 400.1 [M + H].
[Example 9]
± Ethyl 2- (4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine -6-Il acetate Ethyl (E) -3- (5- (3- (2-cyclopropylacetyl) -4,5-dimethylthiophen-2-yl) -1-methyl- in ethanol (5 mL) Ammonium formate (1.26 g, 20.0 mmol) is added to a solution of 2-oxo-1,2-dihydropyridine-4-yl) acrylate (24, 0.2 g, 0.5 mmol) and heated to 90 ° C. did. After 24 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a residue. The crude was purified by combiflash and eluted with 0-10% MeOH: DCM. The pure fraction is concentrated and ethyl 2- (4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] Azepine-6-yl) acetate (0.145 g, 70% yield) was obtained as a pale yellow solid. MS (ESI): _{Mass spectrometry of C 22} H ₂₆ N ₂ O ₃ S, 398.17, m / z, measured value: 399.2 [M + H].
[2- (4- (Cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- Preparation of 6-yl) acetic acid (25)]
Ethyl 2- (4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-Il) Acetate (Example 9, 0.14 mg, 0.35 mmol) was dissolved in methanol (3 mL), 4N sodium hydroxide (0.28 g, 7.0 mmol) was added thereto, and the mixture was stirred at room temperature. .. After 4 hours, the volatiles were removed and the residue was dissolved in water and acidified with 2N hydrochloric acid. The precipitate is collected by filtration, dried and dried 2- (4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c]. Thieno [2,3-e] azepine-6-yl) acetic acid (0.11 g, yield 85%) was obtained as a pale yellow solid. MS (ESI): C ₂₀ H ₂₂ N ₂ O ₃ S mass spectrometry, 370.14, m / z, measured value: 371.2 [M + H].
[Example 10]
± 2-(4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) -N-ethylacetamide 2- (4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [ 2,3-e] Azepine-6-yl) acetic acid (25, 0.105 g, 0.2 mmol) solution and HATU (0.161 g, 0.4 mmol) were taken in DMF (1 mL) and stirred at 25 ° C. .. After 5 minutes, ethylamine (0.1 mL, 1.0 mmol, THF solution) was added and stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a residue. The crude was purified by combiflash and eluted with 0-10% MeOH / DCM. Concentrate the pure fraction to 2- (4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [4,3-c] 2,3-e] Azepine-6-yl) -N-ethylacetamide (0.04 g, yield 35%) was obtained as a pale yellow solid. ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.04 (t, 1H), 7.93 (s, 1H), 6.36 (s, 1H), 4.09 (t, J) = 8Hz, 1H), 3.44 (s, 3H), 3.04-3.00 (m, 2H), 2.96-2.87 (m, 1H), 2.78-2.73 (m) , 1H), 2.65-2.47 (m, 1H), 2.35 (s, 3H), 2.25-2.19 (m, 1H), 2.16 (m, 3H), 0. 96 (t, J = 12Hz, 3H), 0.61 (m, 1H), 0.20-0.14 (m, 2H), -0.09-0.13 (m, 2H). MS (ESI): _{Mass spectrometry of C 22} H ₂₇ N ₃ O ₂ S, 397.18, m / z, measured value: 398.2 [M + H].
[Example 11]
± Ethyl-2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e] Azepine-5-yl) acetate

[± Ethyl-2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e] ] Preparation of azepine-5-yl) acetate]
Ethyl (E) -3- (4'-(4-chlorobenzoyl) -6'-methoxy-1-methyl-6-oxo-1,6-dihydro- [3,] in ethanol (5 mL) in a closed tube Ammonium formate (1.0 g, 15.9 mmol) was added to 3'-bipyridine] -4-yl) acrylate (26, 0.36 g, 0.79 mmol), and the mixture was heated to 90 ° C. After 15 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a residue. The crude was purified by combiflash and eluted with 0-10% MeOH / DCM. The pure fraction was concentrated to give the title compound (0.33 g, 90% yield) as a pale yellow solid. MS (ESI): Mass spectrometry of _{C 24} H _{22 ClN 3} O ₄ , 451.13, m / z, measured value: 452.1 [M + 1].
[Example 12]
± 2-(7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e] azepine- 5-Il) -N-ethylacetamide 0 ° C., dry in a closed tube Ethyl 2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5 in THF (1 mL)) Ethylamine (1.) in a stirred solution of −dihydro-2H-dipyrido [4,3-c: 3', 4'-e] azepine-5-yl) acetate (Example 11, 0.33 g, 0.72 mmol). 8 mL, 3.6 mmol) followed by trimethylaluminum (1M, 4.6 mL, 3.6 mmol). The mixture was stirred at 90 ° C. for 6 hours. The mixture was quenched with saturated ammonium chloride. The residue was distributed in ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified on combiflash (silica gel) by using 0-10% MeOH / DCM and 2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3. , 5-Dihydro-2H-dipyrido [4,3-c: 3', 4'-e] azepine-5-yl) -N-ethylacetamide (0.16 g, yield 45%) was obtained as an off-white solid. .. ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.53 (s, 1H), 8.11-8.04 (m, 2H), 7.50-7.45 (m, 4H) , 6.63 (s, 1H), 6.39 (s, 1H), 4.26 (t, 1H, J = 8Hz, 1H), 3.91 (s, 3H), 3.44 (s, 3H) ), 3.09-3.04 (m, 2H), 2.94-2.92 (m, 2H), 1.00 (t, J = 7.4Hz, 3H)]. MS (ESI): Mass spectrometry of _{C 24} H _{23 ClN 4} O ₃ , 450.15, m / z, measured value: 451.3 [M + 1].
[Preparative chiral HPLC method for separation of enantiomers (u and v)]

Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm)
Monitoring wavelength: 265 nm
Mobile phase: 0.1% DEA in 100% MeOH
[Example 12a]
(S) -2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e ] Azepine-5-yl) -N-ethylacetamide
^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.53 (s, 1H), 8.11-8.04 (m, 2H), 7.50-7.40 (m, 4H) , 6.63 (s, 1H), 6.39 (s, 1H), 4.26 (t, 1H, J = 8Hz, 1H), 3.91 (s, 3H), 3.44 (s, 3H) ), 3.09-3.04 (m, 2H), 2.94-2.92 (m, 2H), 1.00 (t, J = 4Hz, 3H)]. MS (ESI): Mass spectrometry of _{C 24} H _{23 ClN 4} O ₃ , 450.15, m / z actual measurement, 451.3 [M + 1].
[Example 12b]
(R) -2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e ] Azepine-5-yl) -N-ethylacetamide
^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.53 (s, 1H), 8.11-8.04 (m, 2H), 7.45 (m, 4H), 6.63 (S, 1H), 6.39 (s, 1H), 4.26 (t, 1H, J = 8Hz, 1H), 3.91 (s, 3H), 3.44 (s, 3H), 3. 09-3.04 (m, 2H), 2.94-2.92 (m, 2H), 1.00 (t, J = 4Hz, 3H). MS (ESI): Mass spectrometry of _{C 24} H _{23 ClN 4} O ₃ , 450.15, m / z, measured value: 451.3 [M + 1].
[Example 13]
± Ethyl 2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] azepine -6-yl) acetate

[Ethyl (E) -3- (5- (5- (4-chlorobenzoyl) -1-methyl-1H-pyrazole-4-yl) -2-methoxypyridin-4-yl) acrylate (28) Preparation]
In a stirred solution of ethyl (E) -3- (5-bromo-2-methoxypyridin-4-yl) acrylate (27, 3.0 g, 0.011 mol) in toluene (50 mL), (4-chlorophenyl). ) 1-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-5-yl) methanone (intermediate L6, 4.3 g, 0) .013 mol), followed by a saturated NaOHCO ₃ aqueous solution (3.5 g, 0.042 mol), and degassing was performed for 10 minutes. Then, tetrakis (triphenylphosphine) palladium (0) catalyst (2. g, 0.002 mol) was added. The reaction mixture was then refluxed overnight. After completion of the reaction, it was confirmed by TLC, and the reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated, purified with combiflash (silica gel: ethyl acetate / hexane) and the desired compound eluted with 13% EA / hexane. Column fractions containing the required products were collected and evaporated to give the title compound (2.0 g, 45% yield). MS (ESI): Mass spectrometry of _{C 22} H _{20 ClN 3} O ₄ , 425.11, m / z, measured value: 426.1 [M + H] ⁺ .

[Ethyl (E) -3- (5- (5- (4-chlorobenzoyl) -1-methyl-1H-pyrazole-4-yl) -1-methyl-2-oxo-1,2-dihydropyridine-4-yl) Il) Preparation of acrylate (29)]
Ethyl (E) -3- (5- (5- (4-chlorobenzoyl) -1-methyl-1H-pyrazole-4-yl) -2-methoxypyridin-4-yl) acrylic acid in acetonitrile (5 mL) Methyl iodide (1.46 mL, 0.024 mol) was added to a stirred solution of salt (28, 2.0 g, 0.0047 mol). The reaction mixture was heated in a closed tube at 90 ° C. overnight. After completion of the reaction, the mixture was confirmed by TLC, the reaction mixture was concentrated, and purified by combiflash (neutral alumina: MeOH / DCM). The column fraction containing the required product is collected and evaporated and ethyl (E) -3- (5- (5- (4-chlorobenzoyl) -1-methyl-1H-pyrazole-4-yl) -1. -Methyl-2-oxo-1,2-dihydropyridine-4-yl) acrylate (1.0 g, yield 50%) was obtained. MS (ESI): Mass spectrometry of _{C 22} H _{20 ClN 3} O ₄ , 425.11, m / z, measured value: 426.1 [M + H] ⁺ .
[Example 13]
[± Ethyl (Z) -2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-8,9-dihydropyrazolo [3,4-c] pyrido [3,4-e]] Azepine-6 (3H) -iriden) acetate]
Ethyl (E) -3-(5- (5- (4-chlorobenzoyl) -1-methyl-1H-pyrazol-4-yl) -1-methyl-2-oxo-1,2) in EtOH (10 mL) Ammonium formate (1.8 g, 0.0282 mol) was added to a stirred solution of −dihydropyridine-4-yl) acrylate (29, 0.3 g, 0.007 mol) and heated at 85 ° C. overnight. After completion of the reaction, it was confirmed by TLC, ethanol was evaporated, the residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The compounds were purified with Combiflash (neutral alumina: MeOH / DCM) and the desired compound was eluted with 5% MeOH / DCM. Column fractions containing the required products were collected and evaporated to give the title compound (0.08 g, 26% yield). ^{1 1} H NMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.15 (s, 1H), 7.96 (s, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.4Hz, 2H), 6.41 (s, 1H), 4.25 (m, 1H), 4.23-4.04 (m, 2H), 3.45 ( s, 6H), 3.33-3.19 (m, 2H), 1.16 (t, J =, 3H). MS (ESI): Mass spectrometry of _{C 22} H _{19 ClN 4} O ₃ , 424.13, m / z, measured value: 425.2 [M + H] ⁺ .
[2- (4- (4-Chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] azepine- Preparation of 6-yl) acetic acid (30)]
Ethyl (Z) -2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-8,9-dihydropyrazolo [3,4-c] pyridos in MeOH (10 mL) [3,4-c] 4-e] A 4N NaOH solution was added to a solution of azepine-6 (3H) -iriden) acetate (0.3 g, 0.007 mol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was confirmed by TLC, MeOH was evaporated, the residue was dissolved in ethyl acetate, and the mixture was extracted with water. The aqueous layer was acidified to pH 3 with 2N HCl, the precipitate formed was filtered and washed with diethyl ether to give the title compound (0.2 g, 70% yield). MS (ESI): Mass spectrometry of _{C 20} H _{15 ClN 4} O ₃ , 396.10, m / z, measured value: 397.1 [M + H] ⁺ .
[Example 14]
± 2-(4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] azepine- (Z) -2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-8,9-dihydropyrazolo [3,] in 6-yl) -N-ethylacetamide DMF (10 mL) HATU (0.29 g, 0.75 mmol) was added to a stirred solution of 4-c] pyrido [3,4-e] azepine-6 (3H) -iriden) acetic acid (30, 0.2 g, 0.5 mmol). .. After stirring for 5 minutes, ethylamine (0.113 g, 2.5 mmol) was added, followed by DIPEA (0.16 mL, 0.1 mmol), and the reaction mixture was stirred for 30 minutes. After completion of the reaction, after confirmation by TLC, crushed ice was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The compounds were purified with Combiflash (neutral alumina: MeOH / DCM) and the desired compound was eluted with 5% MeOH / DCM. Column fractions containing the required products were collected and evaporated to give the products (0.21 g, 99% yield). MS (ESI): Mass spectrometry of _{C 22} H _{22 ClN 5} O ₂ , 423.15, m / z, measured value: 424.1 [M + H] ⁺ .
[Preparative chiral HPLC method for separation of enantiomers (14a and 14b)]

[Example 14a]
(R) -2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] ] Azepine-6-yl) -N-ethylacetamide
^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.16 (bs, 1H), 8.13 (s, 1H), 7.94 (s, 1H), 7.72 (d, J) = 8.4Hz, 2H), 7.44 (d, J = 8.4Hz, 2H), 6.41 (s, 1H), 4.35 (bs, 1H), 4.00 (s, 3H), 2.89-2.84 (m, 1H), 1.00 (t, J = 7.6Hz, 3H). MS (ESI): C ₂₂ H ₂₂ ClN ₅ O _2, 423.15 mass spectrometry, m / z, actual measurement: 424.1 [M + H] ⁺ .
[Example 14b]
(S) -2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] ] Azepine-6-yl) -N-ethylacetamide
^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.16 (bs, 1H), 8.13 (s, 1H), 7.94 (s, 1H), 7.72 (d, J) = 8.4Hz, 2H), 7.44 (d, J = 8.4Hz, 2H), 6.41 (s, 1H), 4.35 (bs, 1H), 4.00 (s, 3H), 2.89-2.84 (m, 1H), 1.00 (t, J = 7.6Hz, 3H). MS (ESI): Mass spectrometry of _{C 22} H _{22 ClN 5} O _{2 ,} 423.15, m / z, measured value: 424.1 [M + H] ⁺ .
[Example 15]
± Ethyl 2- (4- (4-chlorophenyl) -8-methoxy-2,3-dimethyl-4,6-dihydrothieno [2', 3': 5,6] oxepino [4,3-c] pyridine-6 -Il) acetate

[Preparation of (E) -ethyl 3- (5- (3- (4-chlorobenzoyl) -4,5-dimethylthiophen-2-yl) -2-methoxypyridin-4-yl) acrylate (31) ]
(2-Bromo-4,5-dimethylthiophene-3-yl) (4-chlorophenyl) methanone (intermediate L2, 0.35 g, 1.5 mmol), (E) -ethyl 3- (2-methoxy-5-) (4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-4-yl) Acrylate (Intermediate L1 0.425 g, 1.30 mmol) and 2M sodium bicarbonate A mixture of (0.178 g, 2.12 mmol) was mixed in toluene (20 mL). The mixture was purged with nitrogen gas for 10 minutes. Tetrakis (triphenylphosphine) palladium (0) (0.12 g, 0.0106 mmol) was then added to the mixture and nitrogen gas was purged through the mixture for 5 minutes. The mixture was heated at 105 ° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified on combiflash (silica gel) and eluted with 0-10% methanol in dichloromethane. The pure fraction was concentrated to give the compound as a pale pink liquid (0.388 g, 80%). MS (ESI): C ₂₄ H ₂₂ ClNO ₄ S mass spectrometry, 455.11, m / z, actual measurement: 456.0 [M + H] ⁺ .
[(E) -Ethyl 3- (5-(3-((4-chlorophenyl) (hydroxy) methyl) -4,5-dimethylthiophen-2-yl) -2-methoxypyridin-4-yl) acrylate Preparation of (32) (E) -Ethyl 3- (5- (3- (4-chlorobenzoyl) -4,5-dimethylthiophen-2-yl) -2-methoxypyridin-4-yl) in methanol (20 mL) Il) To a solution of acrylate (31, 0.34 g, 0.75 mmol), cerium (III) chloride heptahydrate (0.418 g, 1.12 mmol) was added, and the mixture was stirred at room temperature for 5 minutes and then at 0 ° C. Sodium borohydride (0.041 g, 1.12 mmol) was added in. After 1 hour, the reaction mixture was diluted with water and ethyl acetate, the organic layer was separated, dried over sodium sulfate and concentrated to give (E) -ethyl 3- (5-(3-((4-chlorophenyl)). (Hydroxy) methyl) -4,5-dimethylthiophene-2-yl) -2-methoxypyridin-4-yl) acrylate (0.27 g, 80%) was obtained as a pale yellow concentrated liquid. MS (ESI): Mass spectrometry of _{C 24} H _{24 ClNO 4} S, 457.11, m / z, measured value: 458.0 [M + H] ⁺ .
[± Ethyl 2- (4- (4-chlorophenyl) -8-methoxy-2,3-dimethyl-4,6-dihydrothieno [2', 3': 5,6] oxepino [4,3-c] pyridine- Preparation of 6-yl) acetate (33)]
(E) -Ethyl 3- (5-(3-((4-chlorophenyl) (hydroxy) methyl) -4,5-dimethylthiophene-2-yl) -2-methoxypyridin-4- in THF (5 mL) A solution of (yl) acrylate (32, 0.26 g, 0.57 mmol) and 1,8-diazabicycloundec-7-ene (0.432 g, 2.84 mmol) was stirred at 25 ° C. After 24 hours, the reaction mixture was concentrated. The residue was purified by combiflash and eluted with 0-10% methanol in dichloromethane. The pure fraction is concentrated and ethyl 2- (4- (4-chlorophenyl) -8-methoxy-2,3-dimethyl-4,6-dihydrothieno [2', 3': 5,6] oxepino [4] , 3-c] Pyridine-6-yl) acetate (0.21 g, 80%) was obtained as a pale pink liquid. ^{1 1} HNMR: (400 MHz, DMSO-d ₆ ) δ (ppm): 8.429 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8. 4,2H), 6.66 (s, 1H), 6.06 (s, 1H), 5.02-4.98 (m, 1H), 4.18 (q, J = 8Hz, 2H), 3 .85 (s, 3H), 3.24-3.19 (m, 1H), 2.91-2.84 (m, 1H), 2.24-2.28 (m, 3H), 1.63 (S, 3H), 1.23 (t, J = 8Hz, 3H). MS (ESI): C ₂₄ H ₂₄ ClNO ₄ S, 457.11, mass spectrometry of m / z, actual measurement: 458.1 [M + H] ⁺ .
[Example 15]
± Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4, 3-c] Pyridine-6-yl) acetate Ethyl 2- (4- (4-chlorophenyl) -8-methoxy-2,3-dimethyl-4,6-dihydrothieno [2', 3', 3 mL) in acetonitrile (3 mL) Methyl iodide (0.08 mL, 1.31 mmol) was added to a solution of': 5,6] oxepino [4,3-c] pyridin-6-yl) acetate (33, 0.2 g, 0.44 mmol). , Heated to 80 ° C. in a closed tube. After 15 hours, the mixture was cooled to room temperature and concentrated to give the crude product. The crude product was purified on combiflash (silica gel) and eluted with 0-10% methanol in dichloromethane. The pure fraction is concentrated and ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] Oxepino [4,3-c] pyridine-6-yl) acetate (0.18 g, 90%) was obtained as a crystalline solid. MS (ESI): Mass spectrometry of _{C 24} H _{24 ClNO 4} S, 457.11, m / z, Measured value: 458.1 [M + H] ⁺ . NMR is not taken.
[± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4, 3-c] Preparation of pyridine-6-yl) acetic acid (34)]
Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3] -C] Pyridine-6-yl) acetate (Example 15, 0.18 g, 0.42 mmol) was dissolved in methanol (5 mL), 4N sodium hydroxide (0.08 g, 2.02 mmol) was added, and room temperature was added. Was stirred with. After removing the volatile substances, the residue was dissolved in water and acidified with 2N hydrochloric acid. The precipitate is collected by filtration and dried to dry 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] Oxepino [4,3-c] pyridine-6-yl) acetic acid (0.15 g, 89%) was obtained as a pale yellow solid. MS (ESI): Mass spectrometry of _{C 22} H _{20 ClNO 4} S, 429.08, m / z, measured value: 430.0 [M + H] ⁺ .
[Example 16]
± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3] -C] Pyridine-6-yl) -N-ethylacetamide 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2' , 3': 5,6] Oxepino [4,3-c] Pyridine-6-yl) Acetic acid (34, 0.145 g, 0.34 mmol) solution and HATU (0.194 g, 0.51 mmol) in DMF ( 1 mL) was taken and stirred at 25 ° C. After 5 minutes, an ethylamine solution (0.344 mL, 0.68 mmol, 2N in THF) was added and stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by combiflash and eluted with 0-10% methanol in dichloromethane. Concentrate the pure fraction and 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5 , 6] Oxepino [4,3-c] Pyridine-6-yl) -N-ethylacetamide (0.11 g, 71%) was obtained as a pale yellow solid, ^{1 1} HNMR: (400 MHz, DMSO) δ (ppm). : 7.99 (t, J = 4Hz, 1H), 7.94 (s, 1H), 7.34 (d, J = 8Hz, 2H), 7.07 (d, J = 8Hz, 1H), 6 .18 (s, 1H), 8.89 (s, 1H), 4.96-4.92 (m, 1H), 3.47 (s, 3H), 3.19-3.09 (m, 2H) ), 2.78-2.73 (m, 1H), 2.58-2.54 (m, 1H), 2.23 (s, 3H) 1.58 (s, 3H), 1.06 (t) , J = 8Hz, 3H). MS (ESI): Mass spectrometry of _{C 24} H _{25 ClN 2} O ₃ S, 456.13, m / z, measured value: 457.1 [M + H].
[Preparative chiral HPLC method for separation of enantiomers cc and dd]

Preparative chiral HPLC method for separation of enantiomers:
Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm)
Monitoring wavelength 295 nm
Mobile phase: n-hexane: 0.1% DEA in ethanol (50:50)
[Example 16a]
2- (4 S , 6S) (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] Oxepino [4,3-c] Pyridine-6-yl) -N-Ethylacetamide
^{1 1} HNMR: (400 MHz, DMSO) δ (ppm): 7.99 (t, J = 4 Hz, 1H), 7.94 (s, 1H), 7.34 (d, J = 8 Hz, 2H), 7. 07 (d, J = 8Hz, 1H), 6.18 (s, 1H), 8.89 (s, 1H), 4.96-4.92 (m, 1H), 3.47 (s, 3H) , 3.19-3.09 (m, 2H), 2.78-2.73 (m, 1H), 2.58-2.54 (m, 1H), 2.23 (s, 3H) 1. 58 (s, 3H), 1.06 (t, J = 8Hz, 3H). MS (ESI): Mass spectrometry of _{C 24} H _{25 ClN 2} O ₃ S, 456.13, m / z, measured value: 457.1 [M + H].
[Example 16b]
2- (4R, 6R) (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3-c] Pyridine-6-yl) -N-ethylacetamide
^{1 1} HNMR: (400 MHz, DMSO) δ (ppm): 7.99 (t, J = 4 Hz, 1H), 7.94 (s, 1H), 7.34 (d, J = 8 Hz, 2H), 7. 07 (d, J = 8Hz, 1H), 6.18 (s, 1H), 8.89 (s, 1H), 4.96-4.92 (m, 1H), 3.47 (s, 3H) , 3.19-3.09 (m, 2H), 2.78-2.73 (m, 1H), 2.58-2.54 (m, 1H), 2.23 (s, 3H) 1. 58 (s, 3H), 1.06 (t, J = 8Hz, 3H). MS (ESI): Mass spectrometry of _{C 24} H _{25 ClN 2} O ₃ S, 456.13, m / z, measured value: 457.1 [M + H].
[Example 17]
± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3] -C] Pyridine-6-yl) acetamide

2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] in DMF (5 mL)] HATU (0.26 g, 0.699 mmol) was added to a solution of oxepino [4,3-c] pyridine-6-yl) acetic acid (0.2 g, 0.466 mmol), and the mixture was stirred at 25 ° C. After 5 minutes, aqueous ammonia (7 mL) was added and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by combiflash and eluted with 0-10% methanol in dichloromethane. Concentrate the pure fraction to 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5 , 6] Oxepino [4,3-c] pyridin-6-yl) acetamide (0.280 g, 58% yield) was obtained as an off-white solid. ^{1 1} HNMR: (400 MHz, DMSO) δ (ppm): 7.93 (s, 1H), 7.48 (s, 1H), 7.34 (d, J = 8 Hz, 2H), 7.09 (d, J = 8Hz, 2H), 6.96 (s, 1H), 6.19 (s, 1H), 5.94 (s, 1H), 4.92 (t, J = 8.0Hz, 1H), 3 .47 (s, 3H), 2.79-2.74 (m, 1H), 2.61-2.55 (m, 1H), 2.30 (s, 3H), 1.59 (s, 3H) ). MS (ESI): Mass spectrometry of _{C 22} H _{21 ClN 2} O ₃ S, 428.1 m / z, measured value: 429.1 [M + 1].
[Preparative chiral HPLC method for separation of enantiomers]

Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm)
UV: 265 nm
Mobile phase: n-hexane: 0.1% DEA in IPA (70:30)
[Example 17a]
2-(( 4S, 6S) -4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] Oxepino [4,3-c] Pyridine-6-yl) acetamide
^{1 1} HNMR: (400 MHz, DMSO) δ (ppm): 7.93 (s, 1H), 7.48 (s, 1H), 7.34 (d, J = 8 Hz, 2H), 7.09 (d, J = 8Hz, 2H), 6.96 (s, 1H), 6.19 (s, 1H), 5.94 (s, 1H), 4.92 (t, J = 8.0Hz, 1H), 3 .47 (s, 3H), 2.79-2.74 (m, 1H), 2.61-2.55 (m, 1H), 2.30 (s, 3H), 1.59 (s, 3H) ). MS (ESI): Mass spectrometry of _{C 22} H _{21 ClN 2} O ₃ S, 428.1 m / z, measured value: 429.1 [M + 1].
[Example 17b]
2-(( 4R, 6R) -4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] Oxepino [4,3-c] Pyridine-6-yl) acetamide
^{1 1} HNMR: (400 MHz, DMSO) δ (ppm): 7.93 (s, 1H), 7.48 (s, 1H), 7.34 (d, J = 8 Hz, 2H), 7.09 (d, J = 8Hz, 2H), 6.96 (s, 1H), 6.19 (s, 1H), 5.94 (s, 1H), 4.92 (t, J = 8.0Hz, 1H), 3 .47 (s, 3H), 2.79-2.74 (m, 1H), 2.61-2.55 (m, 1H), 2.30 (s, 3H), 1.59 (s, 3H) ). MS (ESI): Mass spectrometry of _{C 22} H _{21 ClN 2} O ₃ S, 428.1 m / z, measured value: 429.1 [M + 1].
[Example 18]
± 4- (4-chlorophenyl) -6- (2-hydroxyethyl) -2,3,9-trimethyl-4,9-dihydrothieno [2', 3': 5,6] Oxepino [4,3-c] Pyridine-8 (6H) -on

Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6) in THF (5 mL) ] A solution of oxepino [4,3-c] pyridine-6-yl) acetate (15, 0.5 g, 0.11 mmol) is added at room temperature, then the mixture is heated to 60 ° C. and methanol (3 mL) at this temperature. ) Was added slowly. After 4 hours, the reaction mixture was cooled to room temperature and concentrated to give a residue, which was taken up in ethyl acetate and washed with water. The organic layer was concentrated to give a mass. The crude was purified by combiflash and eluted with 0-10% MeOH / DCM. The pure fraction is concentrated to 4- (4-chlorophenyl) -6- (2-hydroxyethyl) -2,3,9-trimethyl-4,9-dihydrothieno [2', 3': 5,6]. Oxepino [4,3-c] pyridine-8 (6H) -one (0.2 g, 46% yield) white solid was obtained. ^{1 1} HNMR: (400 MHz, DMSO) δ (ppm): 7.92 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H) ), 6.22 (s, 1H), 5.95 (s, 1H), 4.67-4.62 (m, 2H), 3.72-3.64 (m, 2H), 3.47 ( s, 3H), 2.22 (s, 3H), 2.02-1.98 (m, 1H), 1.77-1.71 (m, 1H), 1.59 (s, 3H). MS (ESI): Mass spectrometry of _{C 22} H _{22 ClNO 3} S, 415.10, m / z, measured value: 416.1 [M + 1].
[Preparative chiral HPLC method for separation of enantiomers of Example 17]

Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm)
UV: 265 nm
Mobile phase A: MTBE
Mobile phase B: Ethanol containing 0.1% DEA [Example 18a]
( 4S, 6S) -4- (4-chlorophenyl) -6- (2-hydroxyethyl) -2,3,9-trimethyl-4,9-dihydrothieno [2', 3': 5,6] Oxepino [4] , 3-c] Pyridine-8 (6H) -on
^{1 1} HNMR: (400 MHz, DMSO) δ (ppm): 7.92 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H) ), 6.22 (s, 1H), 5.95 (s, 1H), 4.67-4.62 (m, 2H), 3.72-3.64 (m, 2H), 3.47 ( s, 3H), 2.22 (s, 3H), 2.02-1.98 (m, 1H), 1.77-1.71 (m, 1H), 1.59 (s, 3H). MS (ESI): C ₂₂ H ₂₂ ClNO ₃ S, mass spectrometry of 415.10, m / z, actual measurement: 416.1 [M + 1].
[Example 18b]
( 4R, 6R) -4- (4-chlorophenyl) -6- (2-hydroxyethyl) -2,3,9-trimethyl-4,9-dihydrothieno [2', 3': 5,6] Oxepino [4] , 3-c] Pyridine-8 (6H) -on
^{1 1} HNMR: (400 MHz, DMSO) δ (ppm): 7.92 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H) ), 6.22 (s, 1H), 5.95 (s, 1H), 4.67-4.62 (m, 2H), 3.72-3.64 (m, 2H), 3.47 ( s, 3H), 2.22 (s, 3H), 2.02-1.98 (m, 1H), 1.77-1.71 (m, 1H), 1.59 (s, 3H). MS (ESI): C ₂₂ H ₂₂ ClNO ₃ S, mass spectrometry of 415.10, m / z, actual measurement: 416.1 [M + 1].
[Example 19]
± Ethyl 2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] azepine -6-yl) acetate

Ethyl (E) -3- (5- (5- (4-chlorobenzoyl) -1-methyl-1H-pyrazol-4-yl) -1-methyl-2-oxo-1,2) in MeOH (20 mL) - dihydropyridin over 4-yl) acrylate (29,1.00g, to a stirred solution of _{0.002mol), CeCl 3 · 7H 2} O (1.3g, 0.0035mol) was added. Then, the reaction mixture was cooled to a temperature of −10 ° C. or lower. Next, NaBH ₄ (0.284 g, 0.0075 mol) was added little by little, and the reaction mixture was stirred for 20 minutes. After completion of the reaction, the reaction mixture was confirmed by TLC, the reaction mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. Compounds were purified using Combiflash (neutral alumina, eluent MeOH / DCM). The column fraction containing the required product is collected and evaporated and ethyl (E) -3-(5-(5-((4-chlorophenyl) (hydroxy) methyl) -1-methyl-1H-pyrazole-4-). Ill)-(1-methyl-2-oxo-1,2-dihydropyridine-4-yl) acrylate (1.00 g, 99% yield) was obtained. MS (ESI): C ₂₂ H ₂₂ ClN ₃ mass calculated value of _{O 4, 427.13, m / z} , ^{Found: 428.1 [M + H] +} .
[Example 19]
Ethyl 2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-4,6,8,9-tetrahydro-3H-pyrazolo [4', 3': 5,6] oxepino [4, 3-c] Pyridine-6-yl) acetate (20 mL) (E) -3-(5-(5-((4-chlorophenyl) (hydroxy) methyl) -1-methyl-1H-pyrazol- K2CO3 (1.6 g, 0.011 mol) in a solution of 4-yl) -1-methyl-2-oxo-1,2-dihydropyridine-4-yl) acrylate (35, 1.00 g, 0.002 mol). Was added. After stirring for 5 minutes, DBU (1 mL, 0.0070 mol) was added. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated, extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. Compounds were purified using Combiflash (silica gel, eluent MeOH / DCM). Column fractions containing the required products are collected, evaporated and ethyl 2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-4,6,8,9-tetrahydro-3H- Pyrazolo [4', 3': 5,6] oxepino [4,3-c] pyridin-6-yl) acetate was obtained (purity, 0.3 g, yield 30%). MS (ESI): C ₂₂ H ₂₂ ClN ₃ O ₄ , 427.13 mass spectrometry, m / z, actual measurement: 428.3 [M + H] ⁺ .
[2- (4- (4-Chlorophenyl) -3,9-dimethyl-8-oxo-4,6,8,9-tetrahydro-3H-pyrazolo [4', 3': 5,6] oxepino [4, 3-c] Preparation of pyridine-6-yl) acetic acid (36)]
Ethyl 2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-4,6,8,9-tetrahydro-3H-pyrazolo [4', 3': 5,) in MeOH (10 mL) 6] A 4N NaOH solution was added to a stirring solution of oxepino [4,3-c] pyridine-6-yl) acetate (0.3 g, 0.007 mol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, it was confirmed by TLC, MeOH was evaporated, the residue was dissolved in ethyl acetate, and the mixture was extracted with water. The aqueous layer was acidified to pH 3 with 2N hydrochloric acid. The precipitate is collected by filtration, dried and with a purity of 90.43% 2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-4,6,8,9-tetrahydro-3H-pyrazolo [4,3', 5,6] oxepino [4,3-c] pyridin-6-yl) acetic acid was obtained (0.28 g, 99% yield). MS (ESI): C ₂₀ H ₁₈ ClN ₃ O ₄ mass spectrometry 399.10, m / z, actual measurement: 400.1 [M + H] ⁺ .
[Example 20]
2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-4,6,8,9-tetrahydro-3H-pyrazolo [4', 3': 5,6] oxepino [4,3] -C] Pyridine-6-yl) -N-ethylacetamide 2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-4,6,8,9-tetrahydro in DMF (10 mL) -3H-pyrazolo [4', 3': 5,6] oxepino [4,3-c] pyridin-6-yl) acetic acid (0.1 g, 0.00025 mol) in a stirred solution of HATU (0.145 g, 0) .00037 mol) was added. After stirring for 5 minutes, ethylamine (0.57 g, 0.00125 mol) followed by DIPEA (0.08 mL, 0.0005 mol) was added and the reaction mixture was stirred for 30 minutes. After completion of the reaction, after confirmation by TLC, crushed ice was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by preparative RP-HPLC to give the title compound (0.010 g, 9.3% yield). ^{1 1} HNMR: (400 MHz, DMSO) δ (ppm): 8.09 (s, 1H), 7.99 (m, 1H), 7.74 (s, 1H), 7.39 (d, J = 8 Hz, 2H), 7.11 (d, J = 8.4Hz, 2H), 6.18 (s, 1H), 6.09 (s, 1H), 4.93-4.89 (m, 1H), 3 .46 (s, 3H), 3.08-3.22 (m, 2H), 2.55-2.62 (m, 2H), 1.03 (t, J = 7.2Hz, 3H). ). MS (ESI): Mass spectrometry of _{C 22} H _{23 ClN 4} O ₃ , 426.15, m / z, measured value: 427.1 [M + H] ⁺ .
Biological method [Biological method]
BRD4 AlphaLISA (PerkinElmer)
Compounds were diluted by step-down dilution (final concentration of DMSO was 1%) and added to the wells of a 384-well Optiplate at the desired concentration. 5 nM BDR4-BD1 enzyme (homemade) and 12 nM biotinylated substrate were added to the wells, covered and incubated for 1 hour at room temperature (RT). After 1 hour, 250 ng of GSH acceptor beads were added to the wells and incubated at RT for 1 hour. Then 500 ng of streptavidin donor beads were added and reincubated at RT for 1 hour. Plates were read with a Thermostar reader with 680 nm excitation and 570 nm emission. As detailed above, by testing the compounds for both BRD4 enzyme inhibitory activity was determined IC _50. The activities of the selected compounds are shown in Table 1.
[Anti-cancer activity: AlamaRblue assay]
The effect of the compound on cancer cell growth was measured in a 3-day growth assay using the AML cell line MV4-11 (ATCC). MV4-11 cells were retained in RPMI supplemented with 10% FBS at 37 ° C. and 5% CO2. For compound testing, MV4-11 cells were seeded in 96-well black lower plate at a density of 15,000 cells / well in 100 μL medium and incubated overnight at 37 ° C. Compound dilution series were prepared in DMSO by 3-fold serial dilution from 100 μM to 0.005 μM. The DMSO dilution series was then diluted with medium and the final compound concentration was added to the wells in the range of 10 μM to 0.0005 μM. After addition of the compound, cells were incubated for 72 hours and the number of viable cells was determined using the AlamaRblue assay (Invitrogen) according to the manufacturer's recommended protocol. Fluorescence measurements from the AlamaRblue assay were normalized to DMSO-treated cells and analyzed using GraphPad Prism software with S-curve compatibility to obtain EC50. The activity of the selected compound is shown in Table 1.

[Determination of biomarkers C-Myc and p21 in MV4-11 cells]
The MV4-11 cells were seeded in 24-well plates at a density of 0.2 × 10 ⁶ cells / ml, and incubated overnight at 37 ° C.. Cells were treated with compound at the indicated concentrations and time points. Cells were harvested at the indicated time points and protein extraction was performed using RIPA buffer. For tumor samples, proteins were extracted by homogenizing small pieces of tumor in RIPA buffer. 25-50 μg of protein was separated by SDS-PAGE and subjected to Western blotting. Antibodies to cMYC and p21 were purchased from CellSignaling. Antibodies to β-actin were purchased from Sigma.
[In vivo xenograft model]
The effect of the compound that inhibits the growth of MV4-11 xenograft tumor was evaluated. Briefly, 5 × 10 ⁶ cells of MV4-11 cells diluted 1: 1 with matrigel were injected subcutaneously into the upper abdomen of female nude mice (Charles Rivers Labs). The total volume injected per animal was 200 μL. Mice were observed for about 15-20 days and tumor volume was measured at the same time. Treatment was disclosed after randomization when the average tumor volume was about 100 mm3. Compounds were formulated in 0.02% tween-80, 0.5% methylcellulose and administered by oral forced feeding. Tumors were measured with a pair of calipers three times a week from the time they matched in size, and the tumor volume was calculated according to formula (V) = (LWH) 0.52 (V: volume (mm3), L: length (mm)). , W: width (mm), H: height (mm)). Tumor volume and body weight were measured during the study period until the average tumor volume in each group reached the end point above 1000 mm3. Compounds of formula (I) are considered active when tumor growth inhibition exceeds 50%.

The subject matter is described in considerable detail with reference to that particular embodiment, but other embodiments are possible. Therefore, the spirit and scope of the invention should not be limited to the description of embodiments contained herein.

Claims (16)

A compound of formula (I), or a keto-enol tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.
here,
--- is absent or single bond,
X is selected from -O- or -N-
n is 0 to 6
R ₁ is a heteroatom selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _5-6 aryl, N, O, S. Selected from the group consisting of C _{1-6 heteroaryls and alkoxyalkyls having, where C 1-6} alkyls, C _3-8 cycloalkyls, C _5-6 aryls, C _1-6 heteroaryls are optional. Substituted with one or more groups selected from hydrogen, C _{1-6 alkyl, halogen, OH,}
R ₂ and R ₃ independently contain hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), thioxo (= S), -SO _2- , amino, hydrazino, formyl, C _{1 -6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6} haloalkoxy, _{arylalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 5-6 aryl, C 2- 6} Heterocyclyl, C _1-6 Heteroaryl, Alkoxyamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , -N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _a C (S) R _b- , -SONR _a R _b- , -SO ₂ NR _a R _b -,- _{oR a, OC (O) R} a, -OC (O) NR a R b -, - SR a, are selected from -SOR _a, or _-SO 2 _{R a, wherein,} R a, _{R b,} and _{R c} , Independently Hydrogen, C _1-6 Alkoxy, C _3-8 Cycloalkyl, C _5-6 Aryl, C _5-6 Aryl Alkoxy, C _2-6 Heterocyclyl, C _1-6 Heteroaryl or C _1-6 Hetero Selected from arylalkyl,
R ₄ consists of C _1-6 alkyl, haloalkyl, C _3-8 cycloalkyl, C _{5-6 aryl, C 1-6} heteroaryl having a heteroatom selected from N, O, S, and alkoxyalkyl. Selected from the group, where C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl are optionally hydrogen, C _1-6 alkyl, halogen, OH and cyano. Substituted with one or more groups selected from
Ring A is selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, pyrazolyl, oxazolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, thiadiazolyl or frill.
Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , or- Selected from O-CO-NR ₅ R ₆
R ₅ , R ₆ and R ₇ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl. Here, when R ₅ , R ₆ and R ₇ are substituted, one or more substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), tioxo (= S). ), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 arylalkoxy, C _3-8 cycloalkyl, C _{3 -8} Cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , −N (R _a ) SO ₂ R _b , −NR _a C (O) OR _b , −NR _a R _b , −NR _a C (O) R _b −, NR _a C (S) R _b −, −SONR _{a R b -, - SO 2} NR a R b -, - oR a, OC (O) R a, -OC (O) NR a R b -, - SR a, from -SOR _a, or _-SO 2 _{R a} Selected, where _Ra , R _b and R _c are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C ₂ A compound of formula (I) selected from _-6 heterocyclyl, C _1-6 heteroaryl or C _{1-6 heteroarylalkyl.} A compound of formula (I), or a keto-enol tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.
here,
--- is a single bond,
X is -N-
n is 0 to 6
R ₁ is C _1-6 alkyl, where C _1-6 alkyl is optionally substituted with one or more groups selected from _{hydrogen, C 1-6 alkyl, halogen, OH.}
R ₂ and R ₃ are independently selected from hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy.
R ₄ consists of C _1-6 alkyl, haloalkyl, C _3-8 cycloalkyl, C _{5-6 aryl, C 1-6} heteroaryl having a heteroatom selected from N, O, S, and alkoxyalkyl. Selected from the group, where C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl are optionally hydrogen, C _1-6 alkyl, halogen, OH and cyano. Substituted with one or more groups selected from
Ring A is selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, pyrazolyl, oxazolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, thiadiazolyl or frill.
Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , or- Selected from O-CO-NR ₅ R ₆
R ₅ , R ₆ and R ₇ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl. Here, when R ₅ , R ₆ and R ₇ are substituted, one or more substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), tioxo (= S). ), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 arylalkoxy, C _3-8 cycloalkyl, C _{3 -8} Cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _2-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , −N (R _a ) SO ₂ R _b , −NR _a C (O) OR _b , −NR _a R _b , −NR _a C (O) R _b −, NR _a C (S) R _b −, −SONR _{a R b -, - SO 2} NR a R b -, - oR a, OC (O) R a, -OC (O) NR a R b -, - SR a, from -SOR _a, or _-SO 2 _{R a} Selected, R _a , R _b and R _c are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C _1-6 is selected from heteroaryl or _{C 1-6} heteroaryl alkyl, compounds of formula (I). A compound of formula (I), or a keto-enol tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.
Here --- is absent,
X is -O-, n is 0-6, R ₁ is C _1-6 alkyl, where C _1-6 alkyl is optionally from hydrogen, C _1-6 alkyl, halogen, OH. Substituted with one or more selected groups,
R ₂ and R ₃ are independently selected from hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy.
R ₄ consists of C _1-6 alkyl, haloalkyl, C _3-8 cycloalkyl, C _{5-6 aryl, C 1-6} heteroaryl having a heteroatom selected from N, O, S, and alkoxyalkyl. Selected from the group, where C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl are optionally hydrogen, C _1-6 alkyl, halogen, OH and cyano. Substituted with one or more groups selected from
Ring A is selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl or frill.
Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , or- Selected from O-CO-NR ₅ R ₆
R ₅ , R ₆ and R ₇ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl. Here, when R ₅ , R ₆ and R ₇ are substituted, one or more substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), tioxo (= S). , -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 arylalkoxy, C _3-8 cycloalkyl, C _{3- 8} Cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C ( O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b ,- N (R _a ) SO ₂ R _b , -NR _a C (O) OR _b , -NR _a R _b , -NR _a C (O) R _b- , NR _a C (S) R _b- , -SONR _{a R b -, - SO 2 NR} a R b -, - oR a, OC (O) R a, -OC (O) NR a R b -, - selected from SR _a, -SOR a, or _-SO 2 _{R a} Here, _Ra , R _b and R _c are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6. A compound of formula (I) selected from heterocyclyl, C _1-6 heteroaryl or C _{1-6 heteroarylalkyl.} A compound of formula (I), or a keto-enol tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.
here,
--- is a single bond,
X is -N-
n is 1-2
R ₁ is C _1-4 alkyl
R ₂ and R ₃ are independently selected from hydrogen, C _1-4 alkyl or C _{1-4 alkoxy.}
R ₄ is selected from the group consisting of C _3-8 cycloalkyl or C _{5-6 aryl, where C 3-8} cycloalkyl or C _5-6 aryl is hydrogen, C _1-6 alkyl, halogen and cyano. Substituted with one or more groups selected from
Ring A is selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl or frill.
Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , or -O -CO-NR ₅ R ₆ selected from
R ₅ , R ₆ and R ₇ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl. Here, when R ₅ , R ₆ and R ₇ are substituted, one or more substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), tioxo (= S). ), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 arylalkoxy, C _3-8 cycloalkyl, C _{3 -8} Cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , −N (R _a ) SO ₂ R _b , −NR _a C (O) OR _b , −NR _a R _b , −NR _a C (O) R _b −, NR _a C (S) R _b −, −SONR _{a R b -, - SO 2} NR a R b -, - oR a, OC (O) R a, -OC (O) NR a R b -, - is selected from the SOR _a or _-SO 2 _{R a,} where R _a , R _b and R _c are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C ₁ A compound of formula (I) selected from _-6 heteroaryl or C _{1-6 heteroarylalkyl.} A compound of formula (I), or a keto-enol tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.
here,
--- is absent,
X is -O-
n is 1-2
R ₁ is C _1-4 alkyl
R ₂ and R ₃ are independently selected from hydrogen, C _1-4 alkyl or C _{1-4 alkoxy.}
R ₄ is selected from the group consisting of C _3-8 cycloalkyl or C _{5-6 aryl, where C 3-8} cycloalkyl or C _5-6 aryl is hydrogen, C _1-6 alkyl, halogen and cyano. Substituted with one or more groups selected from
Ring A is selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl or frill.
Z is -CH ₂ OR ₅ , -COOR ₅ or -CONR ₅ R ₆ , -NR ₅ R ₆ , -NR ₅ CO-OR ₆ , -NR ₅ CO-NR ₆ R ₇ , -NR ₅ COR ₆ , or- Selected from O-CO-NR ₅ R ₆
R ₅ , R ₆ and R ₇ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl, C _1-6 heteroaryl, C _3-8 cycloalkyl and C _1-6 alkyl. Here, when R ₅ , R ₆ and R ₇ are substituted, one or more substituents are hydrogen, halogen, hydroxy, nitro, cyano, azide, nitroso, oxo (= O), tioxo (= S). ), -SO _2- , amino, hydrazino, formyl, C _1-6 alkyl, haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _5-6 arylalkoxy, C _3-8 cycloalkyl, C _{3 -8} Cycloalkyloxy, C _5-6 aryl, C _2-6 heterocyclyl, C _1-6 heteroaryl, alkylamino, -COOR _a , -C (O) R _b , -C (S) R _a , -C (O) NR _a R _b , -C (S) NR _a R _b , -NR _a C (O) NR _b R _c , NR _a C (S) NR _b R _c , -N (R _a ) SOR _b , −N (R _a ) SO ₂ R _b , −NR _a C (O) OR _b , −NR _a R _b , −NR _a C (O) R _b −, NR _a C (S) R _b −, −SONR _{a R b -, - SO 2} NR a R b -, - oR a, OC (O) R a, -OC (O) NR a R b -, - SR a, from -SOR _a, or _-SO 2 _{R a} Selected, R _a , R _b and R _c are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 aryl alkyl, C _2-6 heterocyclyl, C _1-6 is selected from heteroaryl or _{C 1-6} heteroaryl alkyl, compounds of formula (I). A compound of formula (I), or a keto-enol tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.
here,
--- is a single bond,
X is -N-
n is 1-2
R ₁ is C ₁ alkyl
R ₂ and R ₃ are independently selected from hydrogen, C _1-2 alkyl or C _{1-2 alkoxy.}
R ₄ is selected from the group consisting of C _3-8 cycloalkyl or C _{5-6 aryl, where C 3-8} cycloalkyl or C _5-6 aryl is hydrogen, C _1-6 alkyl, halogen and cyano. Substituted with one or more groups selected from
Ring A is selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl or pyrazolyl.
Z is selected from -CH ₂ OR _5, -COOR ₅ , -CONR ₅ R ₆ , or -NR ₅ R.
R ₅ and R ₆ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl and C _1-6 alkyl, wherein if R ₅ and R ₆ are substituted, said substitutions. The group is a compound of formula (I) selected from hydrogen, halogen, hydroxy, nitro, cyano or C _{1-6 alkyl.} A compound of formula (I), or a keto-enol tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.
here,
--- is absent,
X is -O-
n is 1-2
R ₁ is C ₁ alkyl
R ₂ and R ₃ are independently selected from hydrogen, C _1-2 alkyl or C _{1-2 alkoxy.}
R ₄ is selected from the group consisting of C _3-8 cycloalkyl or C _{5-6 aryl, where C 3-8} cycloalkyl or C _5-6 aryl is hydrogen, C _1-6 alkyl, halogen and cyano. Substituted with one or more groups selected from
Ring A is selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyridadinyl or pyrazolyl.
Z is selected from -CH ₂ OR _5, -COOR ₅ , -CONR ₅ R ₆ , or -NR ₅ R ₆ .
R ₅ and R ₆ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl and C _1-6 alkyl, wherein if R ₅ and R ₆ are substituted, said substitutions. The group is a compound of formula (I) selected from hydrogen, halogen, hydroxy, nitro, cyano or C _{1-6 alkyl.} A compound of formula (I), or a keto-enol tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.
here,
--- is absent or single bond,
X is selected from -N- or -O-
n is 1-2
R ₁ is C ₁ alkyl
R ₂ and R ₃ are independently selected from hydrogen or C _{1-2 alkyl.}
R ₄ is selected from the group consisting of C _3-8 cycloalkyl or C _{5-6 aryl, where C 3-8} cycloalkyl or C _5-6 aryl is hydrogen, C _1-6 alkyl, halogen and cyano. Substituted with one or more groups selected from
Ring A is selected from thienyl, thiazolyl, pyridinyl, pyrimidinyl,
Z is selected from -CH ₂ OR _5, -COOR ₅ , -CONR ₅ R ₆ , or -NR ₅ R ₆ .
R ₅ and R ₆ are independently selected from hydrogen or substituted or unsubstituted C _5-6 aryl and C _1-6 alkyl, wherein if R ₅ and R ₆ are substituted, said substitutions. The group is a compound of formula (I) selected from hydrogen, halogen, hydroxy, nitro, cyano or C _{1-6 alkyl.} a. ± Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine -6-yl) acetate,
b. ± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) -N-ethylacetamide,
c. (S) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N-ethylacetamide,
d. (R) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N-ethylacetamide,
e. ± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) acetamide,
f. (S) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) acetamide,
g. (R) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) acetamide,
h. ± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) -N- (4-hydroxyphenyl) acetamide,
i. (S) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N- (4-hydroxyphenyl) acetamide,
j. (R) -2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] ] Azepine-6-yl) -N- (4-hydroxyphenyl) acetamide,
k. (R) -2- (4- (4-Cyanophenyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-c] e] Azepine-6-yl) -N-ethylacetamide,
l. ± Ethyl 2- (4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine-6 -Il) acetate,
m. ± 2-(4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine-6- Il) -N-ethylacetamide,
n. (R) -2- (4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine -6-yl) -N-ethylacetamide,
o. (S) -2- (4- (4-chlorophenyl) -2,9-dimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thiazolo [5,4-e] azepine -6-yl) -N-ethylacetamide,
p. ± Ethyl 2- (5- (4-chlorophenyl) -10-methyl-9-oxo-9,10-dihydro-7H-dipyrido [3,2-c: 3', 4'-e] azepine-7-yl ) Acetate,
q. ± Ethyl 2- (4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine -6-yl) acetate,
r. ± 2-(4- (cyclopropylmethyl) -2,3,9-trimethyl-8-oxo-8,9-dihydro-6H-pyrido [4,3-c] thieno [2,3-e] azepine- 6-yl) -N-ethylacetamide,
S. ± Ethyl-2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e] Azepine-5-yl) acetate,
t. ± 2-(7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e] azepine- 5-yl) -N-ethylacetamide,
u. (S) -2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e ] Azepine-5-yl) -N-ethylacetamide,
v. (R) -2- (7- (4-chlorophenyl) -9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido [4,3-c: 3', 4'-e ] Azepine-5-yl) -N-ethylacetamide,
w. ± Ethyl 2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] azepine -6-yl) acetate,
x. ± 2-(4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] azepine- 6-yl) -N-ethylacetamide,
y. (R) -2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] ] Azepine-6-yl) -N-ethylacetamide,
z. (S) -2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] ] Azepine-6-yl) -N-ethylacetamide,
aa. ± Ethyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4, 3-c] Pyridine-6-yl) acetate,
bb. ± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3] -C] Pyridine-6-yl) -N-ethylacetamide,
cc. 2- (4S, 6S) (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3-c] Pyridine-6-yl) -N-ethylacetamide,
dd. 2- (4R, 6R) (4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3-c] Pyridine-6-yl) -N-ethylacetamide,
ee. ± 2-(4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] oxepino [4,3] -C] Pyridine-6-yl) acetamide,
ff. 2-((4S, 6S) -4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] Oxepino [4,3-c] Pyridine-6-yl) acetamide,
gg. 2-((4R, 6R) -4- (4-chlorophenyl) -2,3,9-trimethyl-8-oxo-4,6,8,9-tetrahydrothieno [2', 3': 5,6] Oxepino [4,3-c] Pyridine-6-yl) acetamide,
hh. ± 4- (4-chlorophenyl) -6- (2-hydroxyethyl) -2,3,9-trimethyl-4,9-dihydrothieno [2', 3': 5,6] Oxepino [4,3-c] Pyridine-8 (6H) -on,
ii. 4S, 6S) -4- (4-chlorophenyl) -6- (2-hydroxyethyl) -2,3,9-trimethyl-4,9-dihydrothieno [2', 3': 5,6] Oxepino [4, 3-c] Pyridine-8 (6H) -on,
JJ. (4R, 6R) -4- (4-chlorophenyl) -6- (2-hydroxyethyl) -2,3,9-trimethyl-4,9-dihydrothieno [2', 3': 5,6] Oxepino [4] , 3-c] Pyridine-8 (6H) -on,
kk. ± Ethyl 2- (4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-3,6,8,9-tetrahydropyrazolo [3,4-c] pyrido [3,4-e] azepine -6-yl) acetate, and ll. ± 2-(4- (4-chlorophenyl) -3,9-dimethyl-8-oxo-4,6,8,9-tetrahydro-3H-pyrazolo [4', 3': 5,6] oxepino [4, 3-c] The compound of formula (I) according to claim 1, selected from the group consisting of pyridine-6-yl) -N-ethylacetamide, or its keto-enol tautomer, stereoisomer, Solvation or pharmaceutically acceptable salt. The compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof is optionally combined with one or more other pharmaceutical compositions together with a pharmaceutically acceptable carrier. A pharmaceutical composition to be used in combination. The pharmaceutical composition according to claim 10, wherein the composition is in the form of tablets, capsules, powders, syrups, solutions, aerosols or suspensions. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for inhibiting one or more BET family bromodomains in a cell. A compound or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, in order to inhibit one or more BET family bromo domain in a cell The pharmaceutical composition used . A pharmaceutical composition according to the pharmaceutical composition or claim 10 comprising a compound of any one of claims 1 to 9, for treating diseases mediated by one or more BET family bromodomain It is the pharmaceutical composition used. A pharmaceutical composition according to any one of claims 10, 11, 13, 14, the proliferative disorder or cancer, is used for at least one of the treatment and prevention, pharmaceutical compositions. The compound or composition, in combination with at least one compound selected from a cytotoxic agent or a non-cytotoxic agent, Ru is administered to a mammal in need a pharmaceutical composition according to claim 15 Things .